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Open AccessFeature PaperEditor’s ChoiceReview

Listeria Monocytogenes: A Model Pathogen Continues to Refine Our Knowledge of the CD8 T Cell Response

Department of Molecular Genetics & Microbiology, Center for Infectious Diseases, Stony Brook University, Stony Brook, NY 11790, USA
*
Author to whom correspondence should be addressed.
Pathogens 2018, 7(2), 55; https://doi.org/10.3390/pathogens7020055
Received: 22 April 2018 / Revised: 13 June 2018 / Accepted: 14 June 2018 / Published: 16 June 2018
(This article belongs to the Special Issue Listeria monocytogenes and Its Interactions with the Host)

Abstract

Listeria monocytogenes (Lm) infection induces robust CD8 T cell responses, which play a critical role in resolving Lm during primary infection and provide protective immunity to re-infections. Comprehensive studies have been conducted to delineate the CD8 T cell response after Lm infection. In this review, the generation of the CD8 T cell response to Lm infection will be discussed. The role of dendritic cell subsets in acquiring and presenting Lm antigens to CD8 T cells and the events that occur during T cell priming and activation will be addressed. CD8 T cell expansion, differentiation and contraction as well as the signals that regulate these processes during Lm infection will be explored. Finally, the formation of memory CD8 T cell subsets in the circulation and in the intestine will be analyzed. Recently, the study of CD8 T cell responses to Lm infection has begun to shift focus from the intravenous infection model to a natural oral infection model as the humanized mouse and murinized Lm have become readily available. Recent findings in the generation of CD8 T cell responses to oral infection using murinized Lm will be explored throughout the review. Finally, CD8 T cell-mediated protective immunity against Lm infection and the use of Lm as a vaccine vector for cancer immunotherapy will be highlighted. Overall, this review will provide detailed knowledge on the biology of CD8 T cell responses after Lm infection that may shed light on improving rational vaccine design.
Keywords: Listeria monocytogenes; CD8 T cells; dendritic cells; T cell activation; expansion; differentiation; contraction; and memory formation; resident memory T cells; CD8 T cell-mediated protective immunity; vaccine; cancer immunotherapy Listeria monocytogenes; CD8 T cells; dendritic cells; T cell activation; expansion; differentiation; contraction; and memory formation; resident memory T cells; CD8 T cell-mediated protective immunity; vaccine; cancer immunotherapy

1. Introduction

Listeria monocytogenes (Lm) is a Gram-positive, facultatively anaerobic intracellular bacterium that can cause listeriosis. It is a foodborne pathogen and primarily affects pregnant women, immunocompromised individuals, the young, and the elderly but may also adversely affect otherwise healthy individuals during outbreaks. Lm infection of pregnant women can lead to infection of the fetus and result in fetal resorption, miscarriage or stillbirth, significantly contributing to the high mortality rate of Lm infections. Premature delivery and vertical transmission to the newborn are also serious complications associated with infection during pregnancy. Infections of susceptible populations may result in sepsis, meningitis, and encephalitis, which could be lethal. However, infections of otherwise healthy individuals typically lead to gastroenteritis. While rare, exposure to outbreak levels of Lm in healthy individuals could also be fatal. In the United States, according to the Centers for Disease Control and Prevention and a recent report conducted by United States Department of Agriculture, Lm is the third leading cause of deaths resulting from foodborne diseases and costs approximately 2.6 billion dollars annually, ranking it the third most among foodborne diseases in economic burden [1,2,3]. Lm infects humans by invading the intestinal epithelium after consumption of contaminated food. The bacterial surface protein internalin A (InlA) promotes the invasion of human intestinal epithelium by binding to E-cadherin (Ecad), an adhesion molecule expressed by intestinal epithelial cells [4]. However, InlA does not recognize murine Ecad, and Lm fails to invade mouse intestines efficiently [5], limiting the use of mice as a model for oral Lm infection of humans. Therefore, the understanding of Lm pathogenesis and the immune response to Lm infection has predominantly been obtained after intravenous (i.v.) infection of mice. As such, this review will primarily summarize the knowledge originating from studies performed in i.v. Lm infection models. The more recent generation of transgenic mice expressing a human Ecad or a humanized murine-Ecad and a murinized Lm strain containing mutations in the InlA protein that allow efficient invasion of murine intestines that may be coupled with a natural feeding infection provides more relevant mouse models for oral Lm infection or vaccination of humans [6,7,8,9,10]. Thus, this review will also discuss knowledge gained from oral Lm infection using these mouse models when available.
Innate inflammatory responses are critical for host defense against Lm infection. A hierarchical recruitment and activation of innate immune cells such as dendritic cells (DC) and inflammatory monocytes to the foci of infection coupled with interleukin (IL)-12, IL-18, interferon (IFN)-γ and tumor necrosis factor (TNF)-α production are essential for the early control of Lm infection [11]. However, sterilizing immunity to Lm infection requires T cells [12,13,14]. CD8 T cells, along with CD4 T cells and γδ T cells collaborate to provide optimal protection against Lm infection [9,13,14,15]. Extensive research has been carried out in the past three decades to broaden our understanding of T cell responses to Lm infection. Lm is also a model pathogen to study T cell biology in general because of its ability to induce robust T cell responses that are readily tractable during all phases of the adaptive response [16,17]. This review will focus on the CD8 T cell response to Lm infection, which can be characterized by four phases: (1) priming and activation; (2) clonal expansion and differentiation; (3) contraction; and (4) memory formation (Figure 1). Details of each phase of the CD8 T cell response to Lm infection will be discussed. Specifically, the role of dendritic cell subsets in acquiring and presenting Lm antigens to CD8 T cells and events that occur during CD8 T cell priming and activation will be addressed. Signals that regulate CD8 T cell expansion, differentiation and contraction during Lm infection will be explored. The formation of memory CD8 T cell subsets in the circulation and in the intestine will be analyzed. Additionally, the comparison of the CD8 T cell response after i.v. versus oral Lm infection will be included. Finally, CD8 T cell-mediated protective immunity against Lm infection and the use of Lm as a vaccine vector for cancer immunotherapy will be highlighted.

2. Listeria Monocytogenes (Lm) Acquisition and Presentation by Dendritic Cells (DC)

After i.v. infection, Lm directly enters the blood circulation and rapidly arrives in the marginal zone of the spleen, where it is taken up by macrophage receptor with collagenous structure (MARCO)+ marginal zone macrophages (MZM) and CD169+ marginal metallophilic macrophages (MMM) [18,19,20]. These macrophages are thought to be crucial for the early control of Lm infection as shown by studies using low dose clodronate liposomes to deplete both macrophage subsets [18]. A recent study using transgenic mice expressing human diphtheria toxin receptor under the control of the Cd169 promoter to selectively deplete CD169+ MMM demonstrated that they are the primary line of defense against Lm infection [20]. In the absence of CD169+ MMM, Lm spreads to the red pulp of the spleen, where it rapidly replicates leading to systemic dissemination [20]. CD169+ MMM initially contain Lm in the marginal zone, and Lm is subsequently transported to the T cell zone of the white pulp [21,22]. Several sophisticated studies have shown that basic leucine zipper ATF-like transcription factor 3 (Batf3)-dependent CD8α+ DC are responsible for shuttling Lm to T cell zones of the white pulp [22,23,24]. The translocation of Lm to the T cell zone is a prerequisite for the establishment of a productive infection and the initiation of antigen presentation to CD8 T cells [22,23,24]. Lm appears to be targeted to Batf3-dependent CD8α+ DC by its association with platelets that is dependent on complement C3 and platelet receptor glycoprotein membrane complex Ib (GPIb) [25]. However, a recent study identified a new pathway in which Lm may be targeted to Batf3-dependent CD8α+ DC early after i.v. infection. CD169+ MMM were visualized acquiring Lm in the marginal zone and trans-infecting Batf3-dependent CD8α+ DC to initiate Lm transit to the T cell zone [20]. Thus, in the absence of CD169+ MMMs, Batf3-dependent CD8α+ DC failed to transport Lm to the T cell zone [20]. Whether platelet association directly targets Lm to Batf3-dependent CD8α+ DC or indirectly through CD169+ MMMs remains to be elucidated. In the absence of Batf3-dependent CD8α+ DC, Lm was unable to establish a productive infection in the T cell zone as they were confined to the marginal zone and rapidly cleared by macrophages [20,24]. As such, CD8 T cell responses were also significantly impaired [24]. This impairment could be rescued by increasing infectious dose or adoptive transfer of Lm-infected bone marrow-derived macrophages [23,24], suggesting that Batf3-independent DC are also capable of priming CD8 T cell responses to i.v. Lm infection. However, under normal physiological conditions, Batf3-dependent CD8α+ DC appear to play a central role in the activation of CD8 T cells, which has also been corroborated by in vitro studies showing that CD8α+ DC are more effective than CD11b+ DC at eliciting CD8 T cell responses to Lm [26]. In addition to their role in transporting Lm to the T cell zone and activating CD8 T cells, a new study demonstrated that Batf3-dependent CD8α+ DC are a vital source of IL-18, which subsequently licenses Natural Killer (NK) cells to produce IL-10 [27]. As NK cell-derived IL-10 promotes susceptibility to Lm infection [28], this new study provides an additional mechanism that contributes to the resistance of mice deficient in Batf3-dependent CD8α+ DC to Lm infection.
After oral infection, Lm invades the gut epithelium and disseminates to the draining mesenteric lymph nodes (MLN), a primary site of T cell priming in response to intestinal pathogens. Whether Lm disseminates to the MLN extracellularly or intracellularly remains to be elucidated. While mechanistic in vivo insights of Lm dissemination is lacking, intracellular localization and replication appears essential for Lm dissemination to the MLN [29], suggesting that Lm may disseminate to the MLN intracellularly. Both intestinal CD103+ DC and C-X3-C motif chemokine receptor 1 (CX3CR1)+ mononuclear phagocytes (MP) can sample antigens from the lumen and migrate to the MLN in a C-C motif chemokine receptor (CCR)7-dependent manner [30,31,32,33,34]. CX3CR1+ MP are located close to the intestinal epithelium while CD103+ DC reside deeper in the lamina propria (LP) [33]. CX3CR1+ MP have been reported to capture luminal bacteria by extending transepithelial dendrites into the lumen [30]. CD103+ DC can be recruited to the intestinal epithelium in response to enteropathogen infection and can also capture luminal bacteria using transepithelial dendrites [32]. CD103+ DC may also acquire low molecular weight soluble luminal antigen from small intestine goblet cells through goblet cell-associated antigen passages [34]. A collaboration between CX3CR1+ MP and CD103+ DC has also been reported, where CX3CR1+ MP initially acquire luminal antigens for transfer to CD103+ DC [35]. Lm appears to preferentially target luminally accessible Ecad on goblet cells and utilizes the transcytosis pathway to gain access to the lamina propria [36], implying that CD103+ DC may play a direct role in the acquisition of Lm and the transportation of Lm to the MLN. CD103+ DC can efficiently generate CCR9+ α4β7+ gut-tropic effector CD8 T cells after oral administration of antigen [37]. However, CD103+ DC consist of two distinct subsets, interferon regulatory factor (IRF)8-dependent CD11b CD103+ DC and IRF4-dependent CD11b+ CD103+ DC [38,39,40]. Whether CD11b CD103+ DC, CD11b+ CD103+ DC, or both are important for carriage of Lm to MLN and subsequent T cell priming is unresolved. IRF4-dependent CD11b+ CD103+ DC play a critical role in driving mucosal T helper (Th)17 responses [40], while IRF8-dependent CD11b CD103+ DC induce a Th1 response [41]. Lm can induce either Th1 or Th17 responses dependent on the route of infection. While i.v. Lm infection induces Th1 cells, intranasal Lm infection induces Th17 cells [42]. Our recent study demonstrated that a Th1 response is primarily induced after oral Lm infection [15], suggesting the involvement of CD11b CD103+ DC but not CD11b+ CD103+ DC in the induction of T cell responses after oral Lm infection. However, further work needs to determine whether the acquisition and transit of Lm is uncoupled from T cell priming, in which case one DC subset may acquire and transport Lm to the MLN and another DC subset may prime T cells and generate gut-tropic effector CD8 T cells after oral Lm infection.

3. T Cell Priming and Activation

Circulating naïve CD8 T cells enter secondary lymphoid organs where they quickly survey DC before forming prolonged stable conjugates with DC presenting their cognate antigens [43]. During i.v. Lm infection, antigen-specific CD8 T cells form clusters with DC at the borders of the T and B cell zones in the spleen [44]. Immunological synapses are organized at the interfaces of T cells and DC with apparent polarization of T cell receptor (TCR) and CD8 co-receptor, indicating the initiation of T cell activation. Antigen-specific CD8 T cells increase size, downregulate CD62L, and upregulate CD11a, programmed cell death protein 1 (PD-1) and CD69 [44]. Following priming and activation by DC, antigen-specific CD8 T cells migrate to the T cell zones, where they undergo extensive proliferation before exiting the white pulp via bridging channels for entry into the red pulp and exit from the spleen. For i.v. Lm infection, antigen-specific CD8 T cell responses peak around 7–8 days post infection (dpi) [45,46]. Presumably, during oral infection with mouse-adapted Lm, CD8 T cells in the MLN undergo a similar process including initial priming and activation by DC followed by vigorous proliferation in the T cell zones and rapid egress from the MLN. While Lm enter the spleen within minutes after i.v. infection, Lm access to the MLN from the gut is delayed. Accordingly, antigen-specific CD8 T cell responses peak at around 8–9 dpi after oral Lm infection [47,48].
CD8 T cell priming and activation by DC is a crucial step that ensures the generation of functional effector T cells critical for pathogen clearance by eliminating intracellular reservoirs of infected cells. During i.v. infection, efficient CD8 T cell priming and activation occur after infection with live Lm but not administration of heat-killed Lm (HKLm) [49,50]. Following HKLm administration, CD8 T cells undergo poor proliferation and fail to upregulate activation markers such as CD69 and PD-1 [49,50]. These CD8 T cells also exhibit limited cytolytic activity and impaired cytokine production [49,50]. As a result, immunization with HKLm does not induce protective immunity [49,51,52,53]. Multiple mechanisms may account for inefficient CD8 T cell induction after HKLm administration. CD169+ MMM in the marginal zone of the spleen appear to be the primary cellular niche for Lm early after i.v. infection [20]. DC may directly phagocytose Lm in the marginal zone or indirectly acquire Lm from CD169+ MMM [19,20]. The latter requires recruitment of DC to infected CD169+ MMM, which is dependent on Lm invasion of the cytosol [20]. HKLm fails to escape the phagolysosome and is unable to access the cytosol [54]. Therefore, DC may not acquire sufficient antigen after HKLm administration, impairing their ability to induce a robust CD8 T cell response. In addition, while live Lm is rapidly transported to the T cell zone by DC [22,23,24], HKLm remains in the marginal zone [55], suggesting that DC are unable to carry HKLm to the T cell zone to activate T cells after HKLm administration. Indeed, CD8 T cell-DC cluster formation was not observed after HKLm administration [50]. Finally, HKLm infection induced low levels of the costimulatory molecules CD80 and CD86 on DC [55], and this was independent of the amount of Lm uptake by DC suggesting an intrinsic defect associated with HKLm [54]. CD28-mediated signals delivered by DC expressed CD80 and CD86 are important for CD8 T cell activation and expansion after Lm infection [56]. Furthermore, HKLm fails to induce IFN-α/β production from DC [54]. IFN-β production from live Lm-infected DC induces CD69 expression on CD8 T cells and promotes CD8 T cell proliferation after antigen stimulation [54]. These studies suggest that HKLm is unable to induce fully activated DC that can efficiently prime CD8 T cells. Collectively, these studies indicate that CD8 T cell priming and activation by DC after i.v. Lm infection is a multifaceted process involving DC acquisition of Lm that is capable of phagolysosomal escape followed by adequate DC maturation and efficient migration to the T cell zone.
The acquisition of Lm by DC is distinct after i.v. and oral infection. Compared to splenic DC, LP DC in steady state express higher levels of CD86, suggesting that they are more mature during homeostasis [57] and may have a lower activation threshold. Moreover, LP DC constitutively express CCR7 and readily migrate to the MLN upon antigen uptake [57]. Compared to splenic DC, LP DC selectively induce gut-homing receptor α4β7 and CCR9 expression on CD8 T cells [37], which has a profound impact on the tropism of CD8 T cells. However, whether CD8 T cells are primed and activated differently by DC after oral Lm infection and how that will impact their expansion, contraction, differentiation and memory formation are not well understood.

4. T Cell Expansion, Differentiation and Contraction

Naïve antigen-specific CD8 T cells, present at very low frequencies (~80–1200 cells per mouse), undergo rapid and massive clonal expansion and development of effector functions after priming and activation by DC. A large population of effector cells are mobilized into the blood and migrate to sites of infection to eliminate intracellular pathogens by inducing cytolysis of infected cells. Effector CD8 T cells also produce potent anti-pathogen cytokines to aid in the resolution of infection [58,59]. Following the peak of clonal expansion and pathogen clearance, antigen-specific effector CD8 T cells undergo extensive contraction, during which most effector cells (90–95%) rapidly die through apoptosis restoring homeostasis of the immune system. The remaining effector cells survive to form a long-lived self-renewing memory population that can provide life-long protection against reinfection [60]. Effector CD8 T cells that are fated to die during contraction and those that possess memory potential can be identified based on the dichotomous expression of killer cell lectin-like receptor G1 (KLRG-1) and IL-7Rα (CD127) [61,62,63,64,65]. Naïve CD8 T cells express CD127 but not KLRG-1 [61,62,64,65,66]. Within the first few days after antigen encounter, CD8 T cells downregulate CD127 and form a plastic population of CD127 KLRG-1 early effector cells (EEC) [46,67]. EEC can upregulate KLRG1 to differentiate into CD127 KLRG-1+ short-lived effector cells (SLEC) or reexpress CD127 to differentiate into CD127+ KLRG-1 memory precursor effector cells (MPEC). SLEC are terminally differentiated and undergo apoptosis during immune contraction, while MPEC have long-lived potential and survive into self-maintaining memory cells. In some circumstances, a subset of cells expressing both KLRG-1 and CD127 develop, but their developmental pathway and immunological role are less clear [46,68].
Antigen-specific CD8 T cell expansion and contraction after i.v. Lm infection is instructed during priming [69,70]. However, manipulation of the infection to influence the amount and duration of antigen and inflammation by using antibiotic treatment, attenuated strains or different doses of Lm can greatly impact these processes. Increasing the infectious dose can increase antigen-specific CD8 T cell expansion and the magnitude of the peak response, but it does not appear to affect the onset or early kinetics of contraction [70]. Shortening the length of infection by antibiotic treatment early after infection decreases the magnitude of antigen-specific CD8 T cell expansion [69,70,71,72]. However, the onset of T cell contraction seems to be predominately influenced by the peak of bacterial burden or antigenic load but not the length of infection [72]. Infection with a highly attenuated actin assembly-inducing protein (ActA)-deficient Lm that is not able to spread from cell to cell intracellularly leads to a quicker peak of bacterial load and an accelerated antigen-specific CD8 T cell response with earlier onset of contraction [72]. Continuous treatment of animals with antibiotics before and throughout the infection also significantly impairs the expansion of antigen-specific CD8 T cells [71,73]. Intriguingly, antigen-specific CD8 T cells generated in these antibiotic treated animals do not undergo contraction, leading to a normal and functional memory population despite a substantially reduced effector response. The lack of contraction is thought to be associated with decreased inflammation caused by continuous antibiotic treatment. In such environments, antigen-specific CD8 T cells do not upregulate KLRG-1 to differentiate into SLEC. Instead, they upregulate CD127 and become MPEC that survive and form memory. These studies demonstrate that the inflammatory environment regulates T cell memory differentiation.
CD8 T cell memory differentiation is a continuous process; however, fate decisions occur early during the effector phase at the EEC stage and are largely dictated by the nature of the pathogen and environmental conditions they induce [46,74,75]. After i.v. Lm infection, EEC predominately give rise to SLEC in the spleen, leading to a dominant SLEC population (~75%) with few EEC (~10%) and MPEC (~5%) [46,74,75]. In comparison, after i.v. vesicular stomatitis virus (VSV) infection, some EEC stay undifferentiated and those that differentiate form both SLEC and MPEC in the spleen, resulting in roughly comparable populations of EEC (~35%), SLEC (~35%) and MPEC (~25%) [46,74,75]. The differentiation pattern seen in i.v. VSV infection has also been observed in intranasal influenza A virus infection and vaccinia virus infection via skin scarification [74]. This distinct pathogen-induced differentiation pattern was observed at both the population and single-cell levels [46,74,75]. Moreover, both i.v. and oral Lm infection induced a similar pattern in the spleen with a heavily skewed SLEC population, suggesting that the differentiation pattern of EEC appears pathogen driven [75]. Interestingly, while EEC appear committed to either a SLEC or MPEC fate during priming, they retain plasticity to respond to changing environmental cues [74]. For example, EEC from Lm-infected mice mainly differentiated into SLEC when transferred into naïve mice. However, transfer of Lm-elicited EEC into a mouse infected with VSV expressing the same cognate antigen resulted in a differentiation pattern resembling that observed after VSV infection. Thus, EEC display some level of superficial commitment to a specific lineage based on early signals while maintaining a degree of plasticity to respond appropriately to changing inflammatory cues. This can be further observed in vivo at the single cell level [75]. Unique clones of naïve CD8 T cells that differentiate into effector CD8 T cells with bias to a single developmental pathway can be heavily skewed towards a different development pathway by tissue-specific environments. At the peak of the CD8 T cell response after oral Lm infection, effector CD8 T cells that arose from a single naïve T cell comprised mostly SLEC in the spleen but were heavily skewed towards MPEC and EEC once they migrated into the intestinal epithelium despite being progeny of an identical parent [48,75]. Thus, differentiation patterns can be heavily influenced by the distinct local environments of nonlymphoid tissues.
Pathogen-induced inflammation, when coupled with antigen, critically regulates SLEC and MPEC differentiation [74,76]. Reduced inflammation favors MPEC differentiation, whereas increased inflammation promotes SLEC differentiation [64,71]. I.v. Lm or VSV infection induce distinct inflammatory environments leading to unique differentiation patterns of their effector populations [46]. I.v. Lm infection elicits IL-12, IFN-β and IFN-γ, while VSV infection fails to induce these cytokines. IL-12 signaling promotes antigen-specific CD8 T cell expansion and SLEC differentiation in i.v. Lm infection and CD8 T cells lacking IL-12 receptor have impaired expansion and fail to differentiate into SLEC [46,77]. Mechanistically, IL-12 induces the transcription factor T-bet, which is necessary and sufficient to drive SLEC differentiation [64,78]. IFN-γ signaling can also promote SLEC differentiation following i.v. Lm infection. Antigen-specific CD8 T cells in IFN-γ deficient mice have increased CD127 expression [71]. However, IFN-γ does not induce SLEC differentiation directly [76]. Instead, it influences SLEC differentiation indirectly by promoting IL-12 production [76]. Type I interferon signaling has also been shown to promote antigen-specific CD8 T cell expansion and SLEC differentiation after i.v. Lm infection. CD8 T cells lacking type I interferon receptor fail to undergo robust expansion and cannot efficiently generate SLEC [46]. CD8 T cells lacking both IL-12 receptor and type I interferon receptor have a more profound defect in expansion and SLEC differentiation [46], suggesting that IL-12 and type I interferon play non-redundant roles in driving effector T cell expansion and SLEC differentiation. Overall, i.v. Lm infection favors SLEC differentiation by inducing an environment that promotes SLEC formation.
During i.v. Lm infection, both SLEC and MPEC undergo contraction; however, SLEC contract approximately 10 times more than MPEC [79]. The survival of MPEC is primarily dependent on IL-7, but IL-15 may also contribute to MPEC survival in some contexts [61,62,79]. Both IL-7 and IL-15 promotes cell survival in part by upregulating the expression of the anti-apoptotic molecule Bcl-2 [61,62,80,81], although these cytokines are not interchangeable. While administration of exogenous IL-7 or IL-15 during the contraction phase promotes the survival of MPEC [79], the presence of IL-7 but not IL-15 appears necessary, as MPEC fail to survive in the absence of IL-7 but they survive similarly in the presence or absence of IL-15 [61,62,64]. Thus, while IL-15 may promote MPEC survival, IL-7 is necessary for MPEC survival. The expression of CD127 allows MPEC to survive and form long-lived memory cells in the presence of IL-7; however, it is not sufficient to instruct memory formation as forced CD127 expression on SLEC does not save them from death [82,83]. As SLEC do not express CD127, their survival during contraction is predominantly dependent on IL-15 [64,79,80,81]. In the absence of IL-15, SLEC contract more rapidly, indicating IL-15 promotes some level of SLEC survival during contraction [64,80,81]. However, the ability to sense IL-15 is not sufficient for their long-term survival as SLEC still contract ~20-fold after i.v. Lm infection [79]. The massive contraction of SLEC is induced by transforming growth factor-β (TGF-β), which is upregulated after i.v. Lm infection and selectively promotes the apoptosis of SLEC during clonal expansion and contraction by dampening B-cell lymphoma (Bcl)-2 expression [81]. While both SLEC and MPEC express TGF-β receptor, IL-7 but not IL-15 seems to be able to overcome the apoptotic effect induced by TGF-β. Thus, TGF-β and IL-15 exert opposite roles in controlling the fate of SLEC after i.v. Lm infection.
Oral Lm infection induces similar kinetics of T cell expansion and contraction and a similar differentiation pattern in the spleen as i.v. infection, with the exception that antigen-specific CD8 T cells peak one day later after oral infection [45,46,47,48,75]. However, as discussed above the differentiation pattern can be profoundly impacted by the tissue-specific environment [75]. While antigen-specific CD8 T cells are largely SLEC in the spleen after oral Lm infection, the population rapidly shifts to MPEC in the intestine [48]. It appears SLEC undergo accelerated apoptosis in response to TGF-β signaling in the intestine, leading to the rapid accumulation of MPEC. This suggests that antigen-specific CD8 T cells in the intestine are more susceptible to TGF-β-induced apoptosis or that TGF-β signaling is more abundant in the intestine. Future studies are required to elucidate the detailed mechanisms involved in intestinal CD8 T cell differentiation.

5. T Cell Memory Formation

After pathogen clearance, MPEC that survive the contraction phase give rise to long-lived memory cells. Memory CD8 T cells are heterogenous and have been traditionally divided into central memory T (TCM) cells and effector memory T (TEM) cells based on their migratory patterns [84]. TCM cells express lymph node homing receptors CD62L and CCR7 and circulate between the bloodstream and secondary lymphoid organs. TEM cells lack these receptors and circulate through the bloodstream, permissive non-lymphoid tissues and secondary lymphoid organs. I.v. Lm infection induces rapid generation of CD62L+ TCM cells [85]. CD62L+ cells emerge in a subset of MPEC at the peak of the T cell response and gradually increase over time [85]. The entire antigen-specific CD8 T cell population gradually shifts from CD62L TEM cells to CD62L+ TCM cells. A linear TEM → TCM differentiation pathway had been proposed, in which TEM cells are transitional and give rise to TCM cells [86]. However, this does not appear to be the dominant pathway under normal physiological conditions [87]. CD62L TEM cells generated under abnormally elevated precursor frequencies are not fully committed and capable of re-expressing CD62L and converting to CD62L+ TCM cells. However, under physiological conditions with low precursor frequencies of naïve antigen-specific CD8 T cells, or in adoptive transfer systems where small numbers of naïve TCR transgenic CD8 T cells are used, CD62L TEM and CD62L+ TCM cells appear as distinct and stable lineages that develop independently without interconversion [87]. The gradual shift of the antigen-specific memory CD8 T cell population from CD62L TEM cells to CD62L+ TCM cells occurs due to a higher proliferative capacity of CD62L+ TCM cells leading to their preferential accumulation over time [59,85,87]. Overall, CD62L expression and TEM/TCM lineage commitment is largely influenced by the initial frequency of naïve antigen-specific CD8 T cells [59,87,88]. TEM/TCM lineage decision occurs during the primary immune response [87]. It is generally believed that weak stimulation favors the generation of CD62L+ TCM cells, while strong stimulation is required for CD62L TEM cell generation. Indeed, limiting antigen availability and/or inflammation during i.v. Lm infection by blocking antigen presentation or shortening the infection promotes CD62L+ TCM cell development [85,89]. Both TEM and TCM cells are capable of proliferating, producing cytokines such as IFN-γ and TNF-α and acquiring cytotoxicity upon antigenic stimulation, although TCM cells have greater proliferative capacity and can produce IL-2 [86]. However, their protective capacity for challenge infections is greatly dependent on the characteristics of both the pathogen (i.e., site where the pathogen replicates and activation of T cells occurs) and memory subset (i.e., proliferative capacity and migratory preference) [90,91]. In i.v. Lm challenge infection, both TEM and TCM cells mount recall responses and contribute to protective immunity, with TEM cells providing superior protection [90,92,93].
The identification of tissue-resident memory T (TRM) cells was a breakthrough in the field of memory CD8 T cells [48,94,95,96,97] that substantially improved our understanding of memory CD8 T cell subsets and their protective functions in tissues. Contrary to circulating TEM and TCM cells, TRM cells represent a subset of memory T cells that are self-maintained in tissues without the need for replenishment from the circulation. They are phenotypically, functionally, transcriptionally, and metabolically distinct from TEM and TCM cells [98,99,100,101]. TRM cells do not express CD62L and CCR7; instead, they express CD69, which provides a mechanism promoting their retention in tissues [102,103]. CD69 physically interacts with sphingosine-1-phosphate receptor 1 (S1PR1) and inhibits the S1PR1-mediated egress of CD8 TRM cells from tissues [104,105]. Additionally, some TRM cells also express CD103, which binds Ecad expressed by epithelial cells in barrier tissues and plays an important role in the retention of CD8 TRM cells in barrier tissues [98,106,107]. CD8 TRM cells have been shown to play a critical role in protective immunity against infections and cancers [48,94,95,97,108,109,110]. They are pre-positioned in the tissue to respond immediately to pathogen re-encounter and mediate protective immunity by direct lysis of infected cells or by activating innate immune cells and recruiting circulating memory T cells through the release of cytokines IFN-γ, IL-2 and TNFα [111,112,113]. Recent studies using an oral infection model of Lm demonstrated the robust induction of antigen-specific CD8 T cell responses in the intestine [47,48,114]. These intestinal antigen-specific CD8 T cells quickly adopted an MPEC phenotype and upregulated CD69 and CD103 expression, indicating rapid generation of CD8 TRM cells in the intestine 9 days after oral Lm infection [48]. The expression of CD69 and CD103 was exclusively confined to MPEC, supporting the notion that CD8 TRM cells are derived from MPEC. In this model, CD103 expression promoted the accumulation but not retention of antigen-specific CD8 T cells in the intestinal epithelium [48]. As CD103 also binds Ecad expressed by intestinal epithelial cells, it is possible that CD103 promotion of intestinal accumulation early after infection is due to the nature of Ecad-mediated Lm entry into the intestinal epithelium, and this topic needs further exploration. The rapid generation and maintenance of CD69+ CD103+ CD8 TRM cells in the intestine after oral Lm infection is critically regulated by TGF-β signaling. In the absence of TGF-β signaling, antigen-specific CD8 T cells migrated to the intestine efficiently but failed to become CD69+ CD103+ CD8 TRM cells and were not maintained in the intestine [48]. These intestinal CD8 TRM cells established early after primary oral Lm infection provided optimal protection against secondary oral Lm infection [48]. Compared to oral Lm infection, i.v. Lm infection induced a significantly smaller population of antigen-specific CD8 T cells in the intestine and these CD8 T cells were inefficient at rapidly differentiating into CD69+ CD103+ CD8 TRM cells, suggesting that the route of infection greatly impacts memory CD8 T cell responses in the intestine (our unpublished data). The migration of antigen-specific CD8 T cells to the intestine is controlled by gut-homing receptors α4β7 and CCR9 [115,116]. CD8 T cells induced after oral Lm infection likely express higher levels of α4β7 and CCR9 and migrate more efficiently to the intestine than those induced after i.v. infection as LP DC but not splenic DC selectively instruct CD8 T cells to upregulate α4β7 and CCR9 expression [37], which could contribute to the difference in the magnitude of antigen-specific CD8 T cell responses in the intestine after i.v. and oral infection. However, how infection route regulates the differentiation of CD8 TRM cells in the intestine is unclear. Oral infection likely induces a distinct intestinal environment that may impact in situ differentiation of TRM cells. Overall, i.v. and oral Lm infection appears to induce distinct CD8 cell responses in the intestine, which may greatly impact CD8 TRM cell-mediated immunity. Future studies are required to evaluate the mechanisms governing the induction of superior gastrointestinal CD8 T cell responses after oral infection, which will improve our knowledge of mucosal T cell immunity and provide valuable insights into vaccine design.

6. CD4 T Cell Help

The role of CD4 T cell help in regulating CD8 T cell responses has a long and often contradictory history [117], which is well documented after i.v. Lm infection. Lack of CD4 T cell help has been reported to impair the primary CD8 T cell response [118], the maintenance of memory CD8 T cells [119,120], or the recall CD8 T cell response [118,121]. Alternatively, CD4 T cell help has also been reported to be not critical for the primary CD8 T cell response [49,122], the maintenance of memory CD8 T cells [122], or the recall CD8 T cell response [49,122]. Traditionally, CD4 T cells were envisioned to provide help to CD8 T cells through multiple mechanisms such as activation of antigen presenting cells through CD40L/CD40 interaction (indirect help) or the secretion of IL-2 (direct help). Recently, CD4 T cell help has also been shown to facilitate migration of CD8 T cells into non-lymphoid tissues [123,124]. Whether CD4 T cell help to CD8 T cells during i.v. Lm infection is through CD40L/CD40 interaction is also controversial. While some studies showed that the CD40L–CD40 pathway was not required during the primary or recall CD8 T cell response [122,125,126], others showed that CD40L/CD40 interaction was required for the recall CD8 T cell response [63,118]. However, CD40L/CD40 interaction may provide help to CD8 T cells independently of CD4 T cells [118]. More recently, studies showed that CD4 T cell help induced the expression of CD25 by antigen-specific CD8 T cells, which was required for the optimal SLEC development and effector CD8 T cell expansion in response to IL-2 [127]. Studies further showed that memory CD8 T cells generated in the absence of CD25-mediated signals were able to mount a robust recall response [127], suggesting that CD4 T cell help and IL-2 signaling through CD25 controls the expansion and differentiation of effector CD8 T cells during the primary response but not the recall response.
During oral Lm infection, CD4 T cell help appears to be more important for CD8 T cell response in the intestinal tissues than the spleen and liver during primary response [47], suggesting that CD4 T cells may regulate CD8 T cell responses in a tissue-specific manner. Furthermore, CD4 T cells likely provide help to CD8 T cells through CD40L/CD40 interaction [47]. However, whether CD4 T cell help also regulates the maintenance of memory CD8 T cells and the recall CD8 T cell response after oral Lm infection is unclear.

7. CD8 T Cell-Mediated Protective Immunity against Lm Infection

Once Lm enters the host cell, it is able to use its surface protein ActA to induce actin polymerization and propel itself within the cell and spread to neighboring cells without exposure to the extracellular environment [4]. By remaining intracellular through its lifecycle, Lm can avoid humoral immunity. Thus, sterilizing immunity relies on inducing a robust cellular response [128]. CD8 T cells collaborate with CD4 T cells and γδ T cells to provide optimal protection against Lm infection [9,13,14,15]. The identification of CD8 epitopes from Lm-secreted proteins listeriolysin O (LLO) and invasion-associated protein p60 and the finding that CD8 T cells specific to either of these epitopes can provide protection against Lm infection led to the hypothesis that Lm-secreted proteins may be the most relevant antigens to prime CD8 T cells and to induce protective immunity against Lm infection [17,129,130,131,132,133]. Subsequent studies using recombinant Lm to express a secreted or non-secreted form of epitope derived from lymphocytic choriomeningitis or recombinant Salmonella typhimurium to express secreted or non-secreted forms of LLO and p60 suggested that both secreted and non-secreted epitope or protein can induce primary and secondary antigen-specific CD8 T cell responses [134,135,136]. However, these antigen-specific CD8 T cells provide protection against Lm expressing the secreted antigen but not against Lm expressing a non-secreted form of the same antigen [134,135,136]. Through ActA-mediated cell-to-cell spread, Lm can infect a variety of cells including phagocytic and non-phagocytic cells. In infected phagocytic cells, both secreted and non-secreted bacterial antigens can be presented on the cell surface, while in infected non-phagocytic cells, only secreted bacterial antigens can be displayed on the cell surface for immune surveillance [135]. Therefore, although phagocytic cells can present non-secreted antigens to CD8 T cells to prime them, CD8 T cells specific for non-secreted antigens do not recognize infected non-phagocytic cells and are unable to control listeriosis [135]. As maternal Lm infection can cause serious fetal or neonatal complications, developing prophylactic and therapeutic vaccines against listeriosis is an ongoing interest [137,138,139,140,141,142,143,144]. When designing CD8 T cell-based vaccines against listeriosis, it is important to keep it in mind that non-secreted antigens may not be relevant targets.
Effective control of Lm infection by memory CD8 T cells in the organ where Lm invades may prevent further disseminating infection and limit more serious disease. Lm first invades the spleen or liver after i.v. infection and the intestine after oral infection. These organs contain distinct memory CD8 T cells with unique phenotypes, migratory properties, maintenance requirements, and functions [107,114,145]. Generally, memory CD8 T cells in the intestine express CD69 and some of them also express CD103, both of which are important mediators of tissue residency, while memory CD8 T cells in the spleen lack these markers [107,146]. Memory CD8 T cells in the spleen can circulate through lymphoid tissues or permissive non-lymphoid tissues dependent on their expression of the lymphoid homing receptor CD62L [107,145]. Memory CD8 T cells in the spleen but not intestine express CD122, IL-15 receptor beta, indicating distinct requirements of IL-15 for their maintenance [107,145,147]. Moreover, memory CD8 T cells in the intestine express higher granzyme B but lower IFN-γ, TNF-α and IL-2 compared to memory CD8 T cells in the spleen [107,145], suggesting functional tailoring to the unique tissue environment that may influence their contribution to protective immunity. These phenotypic and functional characteristics seem to be intrinsic to organ-specific environments, as CD8 T cells derived from a single naïve cell acquire different phenotypes when they enter the spleen or intestine [75]. However, the route of infection greatly impacts organ-specific memory CD8 T cell responses. Memory CD8 T cells are enriched in the spleen after i.v. Lm infection while they are enriched in the intestine after oral infection (our unpublished data). CD8 TRM cells provide superior protection against pathogens invading the barrier tissues such as skin, female reproductive tract and lung [94,95,97,148]. Based on this evidence, it is plausible that memory CD8 T cells generated by oral Lm infection provides superior protection against Lm invading the intestine through contaminated food as more CD8 TRM cells would be prepositioned at the location of invasion. Vice versa, it is likely that memory CD8 T cells generated by i.v. Lm infection can protect better against Lm invading the spleen as more memory CD8 T cells would be positioned in the spleen. Whether this same strategy would protect a fetus or neonate is unclear as the route of exposure and even the mediator of fetal resorption is less defined. For example, fetal exposure may occur through direct invasion of extracellular Lm via interaction with placental accessible Ecad [149] or via a trojan horse model where intracellular carriage by circulating immune cells mediates fetal exposure. Intriguingly, a recent study of pregnant mice indicated that CD8 T cells are required for Lm-induced fetal resorption [150]. Depletion of CD8 T cells, neutralization of T cell-derived IFN-γ, or blockade of decidual CD8 T cell accumulation protected against fetal wastage [150]. Thus, strategies aimed at preventing Lm invasion in the intestines may be the best approach to limit fetal and neonatal complications associated with Lm infection during pregnancy. Nevertheless, organ-specific CD8 T cell responses likely shape organ-specific protective immunity. When designing vaccines against listeriosis or other infections and malignancies, it is important to consider the potential benefits of organ-specific immunity.

8. Non-Classical H2-M3-Restricited CD8 T Cell Response

Although most studies focus on major histocompatibility complex (MHC) class Ia (H2-K)-restricted CD8+ T cells, another population of CD8+ T cells that recognizes secreted bacterial-derived N-formylated peptides presented by the nonclassical MHC class Ib molecule H2-M3 responds to Lm infection and distinctly contributes to anti-Lm immunity [151,152,153,154,155]. Despite the limited polymorphism of H2-M3 molecules, several distinct Lm-derived peptides containing N-formyl-methionine have been shown to induce CD8+ T cell responses [153,154,155], with fMIGWII being the major immunodominant epitope during Lm infection [156]. H2-M3-restricted CD8+ T cells express promiscuous antigen receptors which enable them to broadly recognize N-formylated peptides produced by Lm [157,158,159].
I.v. Lm infection results in the generation of both H2-K- and H2-M3-restricted CD8+ T cells; however, these populations differ in their expansion kinetics and memory potential. H2-M3-restricted T cells rapidly and robustly expand in the spleen of infected animals, peaking 2 to 3 days before and outnumbering Lm-specific H2-K-restricted CD8+ T cells during primary infection [156,160,161]. H2-M3-restricted CD8 T cells were functional, displayed high cytotoxic activity and secreted high levels of IFN-γ [161]. Correspondingly, H2-M3-restricted CD8 T cells contribute to protection early during primary Lm infection, at a time when Lm-specific H2-K-restricted CD8+ T cells have not substantially expanded [162]. Although both CD8 T cell populations establish phenotypically similar memory populations and express activation markers upon secondary exposure to Lm [163], only H2-K-restricted memory CD8 T cells dramatically expanded after reinfection [156,160,161]. However, the impaired recall of H2-M3-resticted CD8 T cells appears to be an indirect consequence of the presence of H2-K-restricted memory CD8 T cells. Indeed, an Lm challenge of mice previously immunized with DCs coated with fMIGWII peptide triggered a vigorous expansion of H2-M3-restricted CD8 T cells [164]. However, in this context, H2-M3-restricted memory CD8 T cells were incapable of providing protective immunity to Lm challenge infection [164]. Thus, H2-M3-restricted CD8 T cells form a distinct non-classical CD8 T cell population, whose primarily role is to provide protection early during primary infection enabling sufficient time for the induction of long-term protective H2-K-restricted CD8 T cells. Whether H2-M3-restricted CD8 T cells are induced after oral Lm infection has not been studied.

9. Lm as a Vaccine Vector for Cancer Immunotherapy

Lm has gained prominence as a potential vaccine vector for cancer immunotherapy for several reasons [165,166]. First, Lm displays tumor-homing properties and specifically establishes tropism in primary and metastatic tumors that may result in direct killing of tumor cells [166,167,168,169]. Second, Lm induces a strong innate inflammatory immune response that is key to the induction of potent adaptive immunity and the efficacy of Lm as a cancer vaccine vector [11,165,166]. Third, Lm elicits robust CD8 T cell responses. Lm is able to escape the phagolysosome to gain access to the cytosol of professional antigen-presenting cells where it secretes antigens into the cytosol that are rapidly degraded and efficiently delivered to the MHC class I pathway to activate CD8 T cells [170]. Moreover, recent studies suggested that Lm-derived antigens are processed and presented with greater efficiency compared to endogenously synthesized viral antigens [171], further supporting the use of Lm as a vaccine vector to induce potent CD8 T cell responses. Fourth, Lm-elicited CD8 T cells can overcome tolerance to tumor-associated antigens [172,173], providing the rationale for using Lm as a vaccine vector for cancer immunotherapy. Fifth, Lm-based cancer vaccines have been shown to reduce the number and the suppressive activity of regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment [174,175,176,177], adding another layer of efficacy for Lm-based cancer vaccines. Sixth, Lm vaccines may be repeatedly administered to increase efficacy as antibodies do not appear sufficient to prevent boosting [9]. Finally, Lm is relatively easy to manipulate and a variety of attenuated strains have been created, lessening safety concerns of Lm-based therapeutics [165,166]. Overall, the above features make Lm one of the most promising vaccine vectors for cancer immunotherapy and may also engender Lm-based vaccines to pathogens that have proven difficult to immunize against, such as HIV [178]. Indeed, pre-clinical studies have proven the efficacy of Lm to induce powerful anti-tumoral immunity against a broad range of tumor specific antigens [166,179]. Lm-based cancer vaccines are now undergoing clinical trials for several cancers including pancreatic cancer, cervical cancer, osteosarcoma, colorectal cancer, prostate cancer, lung cancer, and more [166,179,180,181,182,183]. However, most of the pre-clinical studies and clinical trials have used i.v. delivery for Lm-based cancer vaccines as our understanding of Lm-induced immunity has been mainly derived from i.v. infection of mice and questions of whether highly attenuated Lm vaccines can be efficacious when administered orally. Oral infection using mouse-adapted Lm demonstrated that resident memory CD8 T cells rapidly accumulated in the intestinal mucosa and contributed to protection of a challenge infection [48]. Future studies are warranted to investigate the impact of infection route on CD8 T cell responses in different tissues that could lead to more efficacious vaccine delivery modalities tailored to tumor location. For example, an oral vaccine system may be better suited for protection against tumors that require memory populations residing in gastrointestinal tissues for protection as would be the case for pancreatic, small bowel, or colorectal cancers. On the other hand, i.v. immunization may be better utilized for widely distributed cancers or cancers that have metastasized. Even more intriguing is the notion that Lm can be repeatedly administered to boost immune function and this boosting can utilize distinct routes of immunization to tailor the targeting of the immune response as appropriate.

10. Conclusions

Lm is a widely utilized pathogen to study T cell biology due to its ability to induce a potent CD8 T cell response and the availability of immunological tools developed in the past decades. Thus, this pathogen has contributed extensively to our general understanding of T cell biology during an immune response. As Lm induces potent CD8 T cell responses and CD8 tumor-infiltrating lymphocytes play a critical role in mediating anti-tumoral immunity [184,185,186], Lm has become a promising cancer vaccine vector. Dissecting each phase of the CD8 T cell response to Lm infection will broaden our understanding of T cell biology in general and contribute to rational vaccine designs. Future studies to understand how the immunization route regulates organ-specific CD8 T cell responses and how these organ-specific CD8 T cell responses may contribute to enhanced protective immunity may further improve T cell-based vaccine development.

Author Contributions

Writing—Original Draft Preparation, Z.Q.; Writing—Review and Editing, Z.Q., C.K. and B.S.S.

Funding

This research was funded by the National Institutes of Health grant numbers R01 AI076457 (B.S.S.), R21 AI137929 (B.S.S.), K12 GM102778 (Z.Q.), and funds provided by Stony Brook University.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

ActA—actin assembly-inducing protein; Batf3—basic leucine zipper ATF-like transcription factor 3; CCR—C-C motif chemokine receptor; CX3CR1—C-X3-C motif chemokine receptor 1; DC—dendritic cells; dpi—days post infection; Ecad—E-cadherin; EEC—early effector cells; HKLm—heat-killed Lm; IFN—interferon; IL—interleukin; InlA—internalin A; IRF—interferon regulatory factor; i.v.—intravenous; KLRG-1—killer cell lectin-like receptor G1; LLO—listeriolysin O; LmListeria monocytogenes; LP—lamina propria; MARCO—macrophage receptor with collagenous structure; MMM—marginal metallophilic macrophages; MLN—mesenteric lymph nodes; MP—mononuclear phagocytes; MPEC—memory precursor effector cells; MZM—marginal zone macrophages; NK—natural killer; SLEC—short-lived effector cells; TCR—T cell receptor; TCM—central memory T; TEM—effector memory T; Th—T helper; TGF-β—transforming growth factor β; TNF—tumor necrosis factor; TRM—resident memory T; VSV—vesicular stomatitis virus.

References

  1. Scallan, E.; Hoekstra, R.M.; Angulo, F.J.; Tauxe, R.V.; Widdowson, M.; Roy, S.L.; Jones, J.L.; Griffin, P.M. Foodborne Illness Acquired in the United States-Major Pathogens. Emerg. Infect. Dis. 2011, 17, 7–15. [Google Scholar] [CrossRef] [PubMed]
  2. Hoffmann, S.; Batz, M.B.; Morris, J.G., Jr. Annual cost of illness and quality-adjusted life year losses in the United States due to 14 foodborne pathogens. J. Food Prot. 2012, 75, 1292–1302. [Google Scholar] [CrossRef] [PubMed]
  3. Hoffmann, S.; Maculloch, B.; Batz, M. Economic Burden of Major Foodborne Illnesses Acquired in the United States. EIB-140. May 2015; U.S. Department of Agriculture, Economic Research Service: Washington, DC, USA, 2015.
  4. Freitag, N.E.; Port, G.C.; Miner, M.D. Listeria monocytogenes—From saprophyte to intracellular pathogen. Nat. Rev. Microbiol. 2009, 7, 623–628. [Google Scholar] [CrossRef] [PubMed]
  5. Lecuit, M.; Dramsi, S.; Gottardi, C.; Fedor-Chaiken, M.; Gumbiner, B.; Cossart, P. A single amino acid in e-cadherin responsible for host specificity towards the human pathogen Listeria monocytogenes. EMBO J. 1999, 18, 3956–3963. [Google Scholar] [CrossRef] [PubMed]
  6. Lecuit, M.; Vandormael-Pournin, S.; Lefort, J.; Huerre, M.; Gounon, P.; Dupuy, C.; Babinet, C.; Cossart, P. A transgenic model for listeriosis: Role of internalin in crossing the intestinal barrier. Science 2001, 292, 1722–1725. [Google Scholar] [CrossRef] [PubMed]
  7. Disson, O.; Grayo, S.; Huillet, E.; Nikitas, G.; Langa-Vives, F.; Dussurget, O.; Ragon, M.; Le Monnier, A.; Babinet, C.; Cossart, P.; et al. Conjugated action of two species-specific invasion proteins for fetoplacental listeriosis. Nature 2008, 455, 1114–1118. [Google Scholar] [CrossRef] [PubMed]
  8. Wollert, T.; Pasche, B.; Rochon, M.; Deppenmeier, S.; van den Heuvel, J.; Gruber, A.D.; Heinz, D.W.; Lengeling, A.; Schubert, W.D. Extending the host range of Listeria monocytogenes by rational protein design. Cell 2007, 129, 891–902. [Google Scholar] [CrossRef] [PubMed][Green Version]
  9. Sheridan, B.S.; Romagnoli, P.A.; Pham, Q.M.; Fu, H.H.; Alonzo, F., 3rd; Schubert, W.D.; Freitag, N.E.; Lefrancois, L. Gammadelta T cells exhibit multifunctional and protective memory in intestinal tissues. Immunity 2013, 39, 184–195. [Google Scholar] [CrossRef] [PubMed]
  10. Bou Ghanem, E.N.; Jones, G.S.; Myers-Morales, T.; Patil, P.D.; Hidayatullah, A.N.; D’Orazio, S.E. Inla promotes dissemination of Listeria monocytogenes to the mesenteric lymph nodes during food borne infection of mice. PLoS Pathog. 2012, 8, e1003015. [Google Scholar] [CrossRef] [PubMed]
  11. Kang, S.J.; Liang, H.E.; Reizis, B.; Locksley, R.M. Regulation of hierarchical clustering and activation of innate immune cells by dendritic cells. Immunity 2008, 29, 819–833. [Google Scholar] [CrossRef] [PubMed]
  12. Emmerling, P.; Finger, H.; Bockemuhl, J. Listeria monocytogenes infection in nude mice. Infect. Immun. 1975, 12, 437–439. [Google Scholar] [PubMed]
  13. Ladel, C.H.; Flesch, I.E.; Arnoldi, J.; Kaufmann, S.H. Studies with mhc-deficient knock-out mice reveal impact of both mhc i- and mhc ii-dependent T cell responses on Listeria monocytogenes infection. J. Immunol. 1994, 153, 3116–3122. [Google Scholar] [PubMed]
  14. Bhardwaj, V.; Kanagawa, O.; Swanson, P.E.; Unanue, E.R. Chronic listeria infection in SCID mice: Requirements for the carrier state and the dual role of T cells in transferring protection or suppression. J. Immunol. 1998, 160, 376–384. [Google Scholar] [PubMed]
  15. Romagnoli, P.A.; Fu, H.H.; Qiu, Z.; Khairallah, C.; Pham, Q.M.; Puddington, L.; Khanna, K.M.; Lefrancois, L.; Sheridan, B.S. Differentiation of distinct long-lived memory CD4 T cells in intestinal tissues after oral Listeria monocytogenes infection. Mucosal Immunol. 2017, 10, 520–530. [Google Scholar] [CrossRef] [PubMed]
  16. Condotta, S.A.; Richer, M.J.; Badovinac, V.P.; Harty, J.T. Probing CD8 T cell responses with Listeria monocytogenes infection. Adv. Immunol. 2012, 113, 51–80. [Google Scholar] [PubMed]
  17. Khan, S.H.; Badovinac, V.P. Listeria monocytogenes: A model pathogen to study antigen-specific memory CD8 T cell responses. Semin. Immunopathol. 2015, 37, 301–310. [Google Scholar] [CrossRef] [PubMed]
  18. Aichele, P.; Zinke, J.; Grode, L.; Schwendener, R.A.; Kaufmann, S.H.; Seiler, P. Macrophages of the splenic marginal zone are essential for trapping of blood-borne particulate antigen but dispensable for induction of specific T cell responses. J. Immunol. 2003, 171, 1148–1155. [Google Scholar] [CrossRef] [PubMed]
  19. Aoshi, T.; Carrero, J.A.; Konjufca, V.; Koide, Y.; Unanue, E.R.; Miller, M.J. The cellular niche of Listeria monocytogenes infection changes rapidly in the spleen. Eur. J. Immunol. 2009, 39, 417–425. [Google Scholar] [CrossRef] [PubMed]
  20. Perez, O.A.; Yeung, S.T.; Vera-Licona, P.; Romagnoli, P.A.; Samji, T.; Ural, B.B.; Maher, L.; Tanaka, M.; Khanna, K.M. Cd169+ macrophages orchestrate innate immune responses by regulating bacterial localization in the spleen. Sci. Immunol. 2017, 2, eaah5520. [Google Scholar] [CrossRef] [PubMed]
  21. Conlan, J.W. Early pathogenesis of Listeria monocytogenes infection in the mouse spleen. J. Med. Microbiol. 1996, 44, 295–302. [Google Scholar] [CrossRef] [PubMed][Green Version]
  22. Aoshi, T.; Zinselmeyer, B.H.; Konjufca, V.; Lynch, J.N.; Zhang, X.; Koide, Y.; Miller, M.J. Bacterial entry to the splenic white pulp initiates antigen presentation to CD8+ T cells. Immunity 2008, 29, 476–486. [Google Scholar] [CrossRef] [PubMed]
  23. Neuenhahn, M.; Kerksiek, K.M.; Nauerth, M.; Suhre, M.H.; Schiemann, M.; Gebhardt, F.E.; Stemberger, C.; Panthel, K.; Schroder, S.; Chakraborty, T.; et al. Cd8α+ dendritic cells are required for efficient entry of Listeria monocytogenes into the spleen. Immunity 2006, 25, 619–630. [Google Scholar] [CrossRef] [PubMed]
  24. Edelson, B.T.; Bradstreet, T.R.; Hildner, K.; Carrero, J.A.; Frederick, K.E.; Kc, W.; Belizaire, R.; Aoshi, T.; Schreiber, R.D.; Miller, M.J.; et al. Cd8α+ dendritic cells are an obligate cellular entry point for productive infection by Listeria monocytogenes. Immunity 2011, 35, 236–248. [Google Scholar] [CrossRef] [PubMed]
  25. Verschoor, A.; Neuenhahn, M.; Navarini, A.A.; Graef, P.; Plaumann, A.; Seidlmeier, A.; Nieswandt, B.; Massberg, S.; Zinkernagel, R.M.; Hengartner, H.; et al. A platelet-mediated system for shuttling blood-borne bacteria to CD8α+ dendritic cells depends on glycoprotein gpib and complement C3. Nat. Immunol. 2011, 12, 1194–1201. [Google Scholar] [CrossRef] [PubMed]
  26. Kapadia, D.; Sadikovic, A.; Vanloubbeeck, Y.; Brockstedt, D.; Fong, L. Interplay between CD8α+ dendritic cells and monocytes in response to Listeria monocytogenes infection attenuates T cell responses. PLoS ONE 2011, 6, e19376. [Google Scholar] [CrossRef] [PubMed]
  27. Clark, S.E.; Schmidt, R.L.; McDermott, D.S.; Lenz, L.L. A Batf3/Nlrp3/IL-18 Axis Promotes Natural Killer Cell IL-10 Production during Listeria monocytogenes infection. Cell Rep. 2018, 23, 2582–2594. [Google Scholar] [CrossRef] [PubMed]
  28. Clark, S.E.; Filak, H.C.; Guthrie, B.S.; Schmidt, R.L.; Jamieson, A.; Merkel, P.; Knight, V.; Cole, C.M.; Raulet, D.H.; Lenz, L.L. Bacterial manipulation of nk cell regulatory activity increases susceptibility to Listeria monocytogenes infection. PLoS Pathog. 2016, 12, e1005708. [Google Scholar] [CrossRef] [PubMed]
  29. Jones, G.S.; Bussell, K.M.; Myers-Morales, T.; Fieldhouse, A.M.; Bou Ghanem, E.N.; D’Orazio, S.E. Intracellular Listeria monocytogenes comprises a minimal but vital fraction of the intestinal burden following foodborne infection. Infect. Immun. 2015, 83, 3146–3156. [Google Scholar] [CrossRef] [PubMed]
  30. Niess, J.H.; Brand, S.; Gu, X.; Landsman, L.; Jung, S.; McCormick, B.A.; Vyas, J.M.; Boes, M.; Ploegh, H.L.; Fox, J.G.; et al. Cx3cr1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 2005, 307, 254–258. [Google Scholar] [CrossRef] [PubMed]
  31. Diehl, G.E.; Longman, R.S.; Zhang, J.X.; Breart, B.; Galan, C.; Cuesta, A.; Schwab, S.R.; Littman, D.R. Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX3CR1hi cells. Nature 2013, 494, 116–120. [Google Scholar] [CrossRef] [PubMed]
  32. Farache, J.; Koren, I.; Milo, I.; Gurevich, I.; Kim, K.W.; Zigmond, E.; Furtado, G.C.; Lira, S.A.; Shakhar, G. Luminal bacteria recruit CD103+ dendritic cells into the intestinal epithelium to sample bacterial antigens for presentation. Immunity 2013, 38, 581–595. [Google Scholar] [CrossRef] [PubMed]
  33. Schulz, O.; Jaensson, E.; Persson, E.K.; Liu, X.; Worbs, T.; Agace, W.W.; Pabst, O. Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions. J. Exp. Med. 2009, 206, 3101–3114. [Google Scholar] [CrossRef] [PubMed]
  34. McDole, J.R.; Wheeler, L.W.; McDonald, K.G.; Wang, B.; Konjufca, V.; Knoop, K.A.; Newberry, R.D.; Miller, M.J. GobleT cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature 2012, 483, 345–349. [Google Scholar] [CrossRef] [PubMed]
  35. Mazzini, E.; Massimiliano, L.; Penna, G.; Rescigno, M. Oral tolerance can be established via gap junction transfer of fed antigens from CX3CR1+ macrophages to CD103+ dendritic cells. Immunity 2014, 40, 248–261. [Google Scholar] [CrossRef] [PubMed]
  36. Nikitas, G.; Deschamps, C.; Disson, O.; Niault, T.; Cossart, P.; Lecuit, M. Transcytosis of Listeria monocytogenes across the intestinal barrier upon specific targeting of gobleT cell accessible e-cadherin. J. Exp. Med. 2011, 208, 2263–2277. [Google Scholar] [CrossRef] [PubMed]
  37. Johansson-Lindbom, B.; Svensson, M.; Pabst, O.; Palmqvist, C.; Marquez, G.; Forster, R.; Agace, W.W. Functional specialization of gut CD103+ dendritic cells in the regulation of tissue-selective T cell homing. J. Exp. Med. 2005, 202, 1063–1073. [Google Scholar] [CrossRef] [PubMed]
  38. Persson, E.K.; Scott, C.L.; Mowat, A.M.; Agace, W.W. Dendritic cell subsets in the intestinal lamina propria: Ontogeny and function. Eur. J. Immunol. 2013, 43, 3098–3107. [Google Scholar] [CrossRef] [PubMed]
  39. Edelson, B.T.; Kc, W.; Juang, R.; Kohyama, M.; Benoit, L.A.; Klekotka, P.A.; Moon, C.; Albring, J.C.; Ise, W.; Michael, D.G.; et al. Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8α+ conventional dendritic cells. J. Exp. Med. 2010, 207, 823–836. [Google Scholar] [CrossRef] [PubMed]
  40. Persson, E.K.; Uronen-Hansson, H.; Semmrich, M.; Rivollier, A.; Hagerbrand, K.; Marsal, J.; Gudjonsson, S.; Hakansson, U.; Reizis, B.; Kotarsky, K.; et al. IRF4 transcription-factor-dependent CD103+CD11b+ dendritic cells drive mucosal T helper 17 cell differentiation. Immunity 2013, 38, 958–969. [Google Scholar] [CrossRef] [PubMed]
  41. Fujimoto, K.; Karuppuchamy, T.; Takemura, N.; Shimohigoshi, M.; Machida, T.; Haseda, Y.; Aoshi, T.; Ishii, K.J.; Akira, S.; Uematsu, S. A new subset of CD103+CD8α+ dendritic cells in the small intestine expresses TLR3, TLR7, and TLR9 and induces TH1 response and CTL activity. J. Immunol. 2011, 186, 6287–6295. [Google Scholar] [CrossRef] [PubMed]
  42. Pepper, M.; Linehan, J.L.; Pagan, A.J.; Zell, T.; Dileepan, T.; Cleary, P.P.; Jenkins, M.K. Different routes of bacterial infection induce long-lived th1 memory cells and short-lived th17 cells. Nat. Immunol. 2010, 11, 83–89. [Google Scholar] [CrossRef] [PubMed]
  43. Mempel, T.R.; Henrickson, S.E.; Von Andrian, U.H. T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature 2004, 427, 154–159. [Google Scholar] [CrossRef] [PubMed]
  44. Khanna, K.M.; McNamara, J.T.; Lefrancois, L. In situ imaging of the endogenous CD8 T cell response to infection. Science 2007, 318, 116–120. [Google Scholar] [CrossRef] [PubMed]
  45. Busch, D.H.; Pilip, I.M.; Vijh, S.; Pamer, E.G. Coordinate regulation of complex T cell populations responding to bacterial infection. Immunity 1998, 8, 353–362. [Google Scholar] [CrossRef]
  46. Obar, J.J.; Jellison, E.R.; Sheridan, B.S.; Blair, D.A.; Pham, Q.M.; Zickovich, J.M.; Lefrancois, L. Pathogen-induced inflammatory environment controls effector and memory CD8+ T cell differentiation. J. Immunol. 2011, 187, 4967–4978. [Google Scholar] [CrossRef] [PubMed]
  47. Pope, C.; Kim, S.K.; Marzo, A.; Masopust, D.; Williams, K.; Jiang, J.; Shen, H.; Lefrancois, L. Organ-specific regulation of the CD8 T cell response to Listeria monocytogenes infection. J. Immunol. 2001, 166, 3402–3409. [Google Scholar] [CrossRef] [PubMed]
  48. Sheridan, B.S.; Pham, Q.M.; Lee, Y.T.; Cauley, L.S.; Puddington, L.; Lefrancois, L. Oral infection drives a distinct population of intestinal resident memory CD8+ T cells with enhanced protective function. Immunity 2014, 40, 747–757. [Google Scholar] [CrossRef] [PubMed]
  49. Lauvau, G.; Vijh, S.; Kong, P.; Horng, T.; Kerksiek, K.; Serbina, N.; Tuma, R.A.; Pamer, E.G. Priming of memory but not effector CD8 T cells by a killed bacterial vaccine. Science 2001, 294, 1735–1739. [Google Scholar] [CrossRef] [PubMed]
  50. Khanna, K.M.; Blair, D.A.; Vella, A.T.; McSorley, S.J.; Datta, S.K.; Lefrancois, L. T cell and apc dynamics in situ control the outcome of vaccination. J. Immunol. 2010, 185, 239–252. [Google Scholar] [CrossRef] [PubMed]
  51. Von Koenig, C.H.; Finger, H.; Hof, H. Failure of killed Listeria monocytogenes vaccine to produce protective immunity. Nature 1982, 297, 233–234. [Google Scholar] [CrossRef] [PubMed]
  52. Sashinami, H.; Nakane, A.; Iwakura, Y.; Sasaki, M. Effective induction of acquired resistance to Listeria monocytogenes by immunizing mice with in vivo-infected dendritic cells. Infect. Immun. 2003, 71, 117–125. [Google Scholar] [CrossRef] [PubMed]
  53. Datta, S.K.; Okamoto, S.; Hayashi, T.; Shin, S.S.; Mihajlov, I.; Fermin, A.; Guiney, D.G.; Fierer, J.; Raz, E. Vaccination with irradiated listeria induces protective T cell immunity. Immunity 2006, 25, 143–152. [Google Scholar] [CrossRef] [PubMed]
  54. Feng, H.; Zhang, D.; Palliser, D.; Zhu, P.; Cai, S.; Schlesinger, A.; Maliszewski, L.; Lieberman, J. Listeria-infected myeloid dendritic cells produce ifn-beta, priming T cell activation. J. Immunol. 2005, 175, 421–432. [Google Scholar] [CrossRef] [PubMed]
  55. Muraille, E.; Giannino, R.; Guirnalda, P.; Leiner, I.; Jung, S.; Pamer, E.G.; Lauvau, G. Distinct in vivo dendritic cell activation by live versus killed Listeria monocytogenes. Eur. J. Immunol. 2005, 35, 1463–1471. [Google Scholar] [CrossRef] [PubMed]
  56. Mittrucker, H.W.; Kursar, M.; Kohler, A.; Hurwitz, R.; Kaufmann, S.H. Role of CD28 for the generation and expansion of antigen-specific CD8+ t lymphocytes during infection with Listeria monocytogenes. J. Immunol. 2001, 167, 5620–5627. [Google Scholar] [CrossRef] [PubMed]
  57. Jang, M.H.; Sougawa, N.; Tanaka, T.; Hirata, T.; Hiroi, T.; Tohya, K.; Guo, Z.; Umemoto, E.; Ebisuno, Y.; Yang, B.G.; et al. CCR7 is critically important for migration of dendritic cells in intestinal lamina propria to mesenteric lymph nodes. J. Immunol. 2006, 176, 803–810. [Google Scholar] [CrossRef] [PubMed]
  58. Blattman, J.N.; Antia, R.; Sourdive, D.J.; Wang, X.; Kaech, S.M.; Murali-Krishna, K.; Altman, J.D.; Ahmed, R. Estimating the precursor frequency of naive antigen-specific CD8 T cells. J. Exp. Med. 2002, 195, 657–664. [Google Scholar] [CrossRef] [PubMed]
  59. Obar, J.J.; Khanna, K.M.; Lefrancois, L. Endogenous naive CD8+ T cell precursor frequency regulates primary and memory responses to infection. Immunity 2008, 28, 859–869. [Google Scholar] [CrossRef] [PubMed]
  60. Hand, T.W.; Kaech, S.M. Intrinsic and extrinsic control of effector T cell survival and memory T cell development. Immunol. Res. 2009, 45, 46–61. [Google Scholar] [CrossRef] [PubMed]
  61. Schluns, K.S.; Kieper, W.C.; Jameson, S.C.; Lefrancois, L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat. Immunol. 2000, 1, 426–432. [Google Scholar] [CrossRef] [PubMed]
  62. Kaech, S.M.; Tan, J.T.; Wherry, E.J.; Konieczny, B.T.; Surh, C.D.; Ahmed, R. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat. Immunol. 2003, 4, 1191–1198. [Google Scholar] [CrossRef] [PubMed]
  63. Huster, K.M.; Busch, V.; Schiemann, M.; Linkemann, K.; Kerksiek, K.M.; Wagner, H.; Busch, D.H. Selective expression of IL-7 receptor on memory T cells identifies early CD40L-dependent generation of distinct CD8+ memory T cell subsets. Proc. Natl. Acad. Sci. USA 2004, 101, 5610–5615. [Google Scholar] [CrossRef] [PubMed]
  64. Joshi, N.S.; Cui, W.; Chandele, A.; Lee, H.K.; Urso, D.R.; Hagman, J.; Gapin, L.; Kaech, S.M. Inflammation directs memory precursor and short-lived effector CD8+ T cell fates via the graded expression of T-bet transcription factor. Immunity 2007, 27, 281–295. [Google Scholar] [CrossRef] [PubMed]
  65. Sarkar, S.; Kalia, V.; Haining, W.N.; Konieczny, B.T.; Subramaniam, S.; Ahmed, R. Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates. J. Exp. Med. 2008, 205, 625–640. [Google Scholar] [CrossRef] [PubMed][Green Version]
  66. Sheridan, B.S.; Lefrancois, L. Regional and mucosal memory T cells. Nat. Immunol. 2011, 12, 485–491. [Google Scholar] [CrossRef] [PubMed][Green Version]
  67. Lefrancois, L.; Obar, J.J. Once a killer, always a killer: From cytotoxic T cell to memory cell. Immunol. Rev. 2010, 235, 206–218. [Google Scholar] [CrossRef] [PubMed]
  68. Herndler-Brandstetter, D.; Ishigame, H.; Shinnakasu, R.; Plajer, V.; Stecher, C.; Zhao, J.; Lietzenmayer, M.; Kroehling, L.; Takumi, A.; Kometani, K.; et al. Klrg1+ effector CD8+ T cells lose klrg1, differentiate into all memory T cell lineages, and convey enhanced protective immunity. Immunity 2018, 48, 716–729. [Google Scholar] [CrossRef] [PubMed]
  69. Mercado, R.; Vijh, S.; Allen, S.E.; Kerksiek, K.; Pilip, I.M.; Pamer, E.G. Early programming of T cell populations responding to bacterial infection. J. Immunol. 2000, 165, 6833–6839. [Google Scholar] [CrossRef] [PubMed]
  70. Badovinac, V.P.; Porter, B.B.; Harty, J.T. Programmed contraction of CD8+ T cells after infection. Nat. Immunol. 2002, 3, 619–626. [Google Scholar] [CrossRef] [PubMed]
  71. Badovinac, V.P.; Porter, B.B.; Harty, J.T. Cd8+ T cell contraction is controlled by early inflammation. Nat. Immunol. 2004, 5, 809–817. [Google Scholar] [CrossRef] [PubMed]
  72. Porter, B.B.; Harty, J.T. The onset of CD8+-T-cell contraction is influenced by the peak of Listeria monocytogenes infection and antigen display. Infect. Immun. 2006, 74, 1528–1536. [Google Scholar] [CrossRef] [PubMed]
  73. Badovinac, V.P.; Harty, J.T. Manipulating the rate of memory CD8+ T cell generation after acute infection. J. Immunol. 2007, 179, 53–63. [Google Scholar] [CrossRef] [PubMed]
  74. Plumlee, C.R.; Obar, J.J.; Colpitts, S.L.; Jellison, E.R.; Haining, W.N.; Lefrancois, L.; Khanna, K.M. Early effector CD8 T cells display plasticity in populating the short-lived effector and memory-precursor pools following bacterial or viral infection. Sci. Rep. 2015, 5, 12264. [Google Scholar] [CrossRef] [PubMed]
  75. Plumlee, C.R.; Sheridan, B.S.; Cicek, B.B.; Lefrancois, L. Environmental cues dictate the fate of individual CD8+ T cells responding to infection. Immunity 2013, 39, 347–356. [Google Scholar] [CrossRef] [PubMed]
  76. Cui, W.; Joshi, N.S.; Jiang, A.; Kaech, S.M. Effects of signal 3 during CD8 T cell priming: Bystander production of IL-12 enhances effector T cell expansion but promotes terminal differentiation. Vaccine 2009, 27, 2177–2187. [Google Scholar] [CrossRef] [PubMed]
  77. Keppler, S.J.; Theil, K.; Vucikuja, S.; Aichele, P. Effector T-cell differentiation during viral and bacterial infections: Role of direct IL-12 signals for cell fate decision of CD8+ T cells. Eur. J. Immunol. 2009, 39, 1774–1783. [Google Scholar] [CrossRef] [PubMed]
  78. Takemoto, N.; Intlekofer, A.M.; Northrup, J.T.; Wherry, E.J.; Reiner, S.L. Cutting edge: IL-12 inversely regulates T-bet and eomesodermin expression during pathogen-induced CD8+ T cell differentiation. J. Immunol. 2006, 177, 7515–7519. [Google Scholar] [CrossRef] [PubMed]
  79. Rubinstein, M.P.; Lind, N.A.; Purton, J.F.; Filippou, P.; Best, J.A.; McGhee, P.A.; Surh, C.D.; Goldrath, A.W. IL-7 and IL-15 differentially regulate CD8+ T-cell subsets during contraction of the immune response. Blood 2008, 112, 3704–3712. [Google Scholar] [CrossRef] [PubMed]
  80. Yajima, T.; Yoshihara, K.; Nakazato, K.; Kumabe, S.; Koyasu, S.; Sad, S.; Shen, H.; Kuwano, H.; Yoshikai, Y. IL-15 regulates CD8+ T cell contraction during primary infection. J. Immunol. 2006, 176, 507–515. [Google Scholar] [CrossRef] [PubMed]
  81. Sanjabi, S.; Mosaheb, M.M.; Flavell, R.A. Opposing effects of TGF-β and IL-15 cytokines control the number of short-lived effector CD8+ T cells. Immunity 2009, 31, 131–144. [Google Scholar] [CrossRef] [PubMed]
  82. Hand, T.W.; Morre, M.; Kaech, S.M. Expression of IL-7 receptor α is necessary but not sufficient for the formation of memory CD8 T cells during viral infection. Proc. Natl. Acad. Sci. USA 2007, 104, 11730–11735. [Google Scholar] [CrossRef] [PubMed]
  83. Haring, J.S.; Jing, X.; Bollenbacher-Reilley, J.; Xue, H.H.; Leonard, W.J.; Harty, J.T. Constitutive expression of IL-7 receptor α does not support increased expansion or prevent contraction of antigen-specific CD4 or CD8 T cells following Listeria monocytogenes infection. J. Immunol. 2008, 180, 2855–2862. [Google Scholar] [CrossRef] [PubMed]
  84. Sallusto, F.; Lenig, D.; Forster, R.; Lipp, M.; Lanzavecchia, A. Two subsets of memory t lymphocytes with distinct homing potentials and effector functions. Nature 1999, 401, 708–712. [Google Scholar] [CrossRef] [PubMed]
  85. Obar, J.J.; Lefrancois, L. Early signals during CD8 T cell priming regulate the generation of central memory cells. J. Immunol. 2010, 185, 263–272. [Google Scholar] [CrossRef] [PubMed]
  86. Wherry, E.J.; Teichgraber, V.; Becker, T.C.; Masopust, D.; Kaech, S.M.; Antia, R.; von Andrian, U.H.; Ahmed, R. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat. Immunol. 2003, 4, 225–234. [Google Scholar] [CrossRef] [PubMed]
  87. Marzo, A.L.; Klonowski, K.D.; Le Bon, A.; Borrow, P.; Tough, D.F.; Lefrancois, L. Initial T cell frequency dictates memory CD8+ T cell lineage commitment. Nat. Immunol. 2005, 6, 793–799. [Google Scholar] [CrossRef] [PubMed]
  88. Badovinac, V.P.; Haring, J.S.; Harty, J.T. Initial T cell receptor transgenic cell precursor frequency dictates critical aspects of the CD8+ T cell response to infection. Immunity 2007, 26, 827–841. [Google Scholar] [CrossRef] [PubMed]
  89. Williams, M.A.; Bevan, M.J. Shortening the infectious period does not alter expansion of CD8 T cells but diminishes their capacity to differentiate into memory cells. J. Immunol. 2004, 173, 6694–6702. [Google Scholar] [CrossRef] [PubMed]
  90. Klonowski, K.D.; Marzo, A.L.; Williams, K.J.; Lee, S.J.; Pham, Q.M.; Lefrancois, L. Cd8 T cell recall responses are regulated by the tissue tropism of the memory cell and pathogen. J. Immunol. 2006, 177, 6738–6746. [Google Scholar] [CrossRef] [PubMed]
  91. Bachmann, M.F.; Wolint, P.; Schwarz, K.; Jager, P.; Oxenius, A. Functional properties and lineage relationship of CD8+ T cell subsets identified by expression of IL-7 receptor α and CD62L. J. Immunol. 2005, 175, 4686–4696. [Google Scholar] [CrossRef] [PubMed]
  92. Huster, K.M.; Koffler, M.; Stemberger, C.; Schiemann, M.; Wagner, H.; Busch, D.H. Unidirectional development of CD8+ central memory T cells into protective listeria-specific effector memory T cells. Eur. J. Immunol. 2006, 36, 1453–1464. [Google Scholar] [CrossRef] [PubMed]
  93. Olson, J.A.; McDonald-Hyman, C.; Jameson, S.C.; Hamilton, S.E. Effector-like CD8+ T cells in the memory population mediate potent protective immunity. Immunity 2013, 38, 1250–1260. [Google Scholar] [CrossRef] [PubMed]
  94. Gebhardt, T.; Wakim, L.M.; Eidsmo, L.; Reading, P.C.; Heath, W.R.; Carbone, F.R. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat. Immunol. 2009, 10, 524–530. [Google Scholar] [CrossRef] [PubMed]
  95. Jiang, X.; Clark, R.A.; Liu, L.; Wagers, A.J.; Fuhlbrigge, R.C.; Kupper, T.S. Skin infection generates non-migratory memory CD8+ TRM cells providing global skin immunity. Nature 2012, 483, 227–231. [Google Scholar] [CrossRef] [PubMed]
  96. Masopust, D.; Choo, D.; Vezys, V.; Wherry, E.J.; Duraiswamy, J.; Akondy, R.; Wang, J.; Casey, K.A.; Barber, D.L.; Kawamura, K.S.; et al. Dynamic T cell migration program provides resident memory within intestinal epithelium. J. Exp. Med. 2010, 207, 553–564. [Google Scholar] [CrossRef] [PubMed][Green Version]
  97. Wu, T.; Hu, Y.; Lee, Y.T.; Bouchard, K.R.; Benechet, A.; Khanna, K.; Cauley, L.S. Lung-resident memory CD8 T cells (TRM) are indispensable for optimal cross-protection against pulmonary virus infection. J. Leukoc. Biol. 2014, 95, 215–224. [Google Scholar] [CrossRef] [PubMed]
  98. Mackay, L.K.; Rahimpour, A.; Ma, J.Z.; Collins, N.; Stock, A.T.; Hafon, M.L.; Vega-Ramos, J.; Lauzurica, P.; Mueller, S.N.; Stefanovic, T.; et al. The developmental pathway for CD103+CD8+ tissue-resident memory T cells of skin. Nat. Immunol. 2013, 14, 1294–1301. [Google Scholar] [CrossRef] [PubMed]
  99. Wakim, L.M.; Woodward-Davis, A.; Liu, R.; Hu, Y.; Villadangos, J.; Smyth, G.; Bevan, M.J. The molecular signature of tissue resident memory CD8 T cells isolated from the brain. J. Immunol. 2012, 189, 3462–3471. [Google Scholar] [CrossRef] [PubMed]
  100. Mackay, L.K.; Minnich, M.; Kragten, N.A.; Liao, Y.; Nota, B.; Seillet, C.; Zaid, A.; Man, K.; Preston, S.; Freestone, D.; et al. Hobit and blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes. Science 2016, 352, 459–463. [Google Scholar] [CrossRef] [PubMed]
  101. Pan, Y.; Tian, T.; Park, C.O.; Lofftus, S.Y.; Mei, S.; Liu, X.; Luo, C.; O’Malley, J.T.; Gehad, A.; Teague, J.E.; et al. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature 2017, 543, 252–256. [Google Scholar] [CrossRef] [PubMed][Green Version]
  102. Mackay, L.K.; Braun, A.; Macleod, B.L.; Collins, N.; Tebartz, C.; Bedoui, S.; Carbone, F.R.; Gebhardt, T. Cutting edge: Cd69 interference with sphingosine-1-phosphate receptor function regulates peripheral T cell retention. J. Immunol. 2015, 194, 2059–2063. [Google Scholar] [CrossRef] [PubMed]
  103. Skon, C.N.; Lee, J.Y.; Anderson, K.G.; Masopust, D.; Hogquist, K.A.; Jameson, S.C. Transcriptional downregulation of S1PR1 is required for the establishment of resident memory CD8+ T cells. Nat. Immunol. 2013, 14, 1285–1293. [Google Scholar] [CrossRef] [PubMed]
  104. Shiow, L.R.; Rosen, D.B.; Brdickova, N.; Xu, Y.; An, J.; Lanier, L.L.; Cyster, J.G.; Matloubian, M. CD69 acts downstream of interferon-α/β to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature 2006, 440, 540–544. [Google Scholar] [CrossRef] [PubMed]
  105. Bankovich, A.J.; Shiow, L.R.; Cyster, J.G. CD69 suppresses sphingosine 1-Phosophate Receptor-1 (S1P1) function through interaction with membrane helix 4. J. Biol. Chem. 2010, 285, 22328–22337. [Google Scholar] [CrossRef] [PubMed]
  106. Lee, Y.T.; Suarez-Ramirez, J.E.; Wu, T.; Redman, J.M.; Bouchard, K.; Hadley, G.A.; Cauley, L.S. Environmental and antigen receptor-derived signals support sustained surveillance of the lungs by pathogen-specific cytotoxic T lymphocytes. J. Virol. 2011, 85, 4085–4094. [Google Scholar] [CrossRef] [PubMed]
  107. Casey, K.A.; Fraser, K.A.; Schenkel, J.M.; Moran, A.; Abt, M.C.; Beura, L.K.; Lucas, P.J.; Artis, D.; Wherry, E.J.; Hogquist, K.; et al. Antigen-independent differentiation and maintenance of effector-like resident memory T cells in tissues. J. Immunol. 2012, 188, 4866–4875. [Google Scholar] [CrossRef] [PubMed]
  108. Ganesan, A.P.; Clarke, J.; Wood, O.; Garrido-Martin, E.M.; Chee, S.J.; Mellows, T.; Samaniego-Castruita, D.; Singh, D.; Seumois, G.; Alzetani, A.; et al. Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer. Nat. Immunol. 2017, 18, 940–950. [Google Scholar] [CrossRef] [PubMed]
  109. Malik, B.T.; Byrne, K.T.; Vella, J.L.; Zhang, P.; Shabaneh, T.B.; Steinberg, S.M.; Molodtsov, A.K.; Bowers, J.S.; Angeles, C.V.; Paulos, C.M.; et al. Resident memory T cells in the skin mediate durable immunity to melanoma. Sci. Immunol. 2017, 2, eaam6346. [Google Scholar] [CrossRef] [PubMed][Green Version]
  110. Nizard, M.; Roussel, H.; Diniz, M.O.; Karaki, S.; Tran, T.; Voron, T.; Dransart, E.; Sandoval, F.; Riquet, M.; Rance, B.; et al. Induction of resident memory T cells enhances the efficacy of cancer vaccine. Nat. Commun. 2017, 8, 15221. [Google Scholar] [CrossRef] [PubMed][Green Version]
  111. Schenkel, J.M.; Fraser, K.A.; Vezys, V.; Masopust, D. Sensing and alarm function of resident memory CD8+ T cells. Nat. Immunol. 2013, 14, 509–513. [Google Scholar] [CrossRef] [PubMed]
  112. Schenkel, J.M.; Fraser, K.A.; Beura, L.K.; Pauken, K.E.; Vezys, V.; Masopust, D. T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science 2014, 346, 98–101. [Google Scholar] [CrossRef] [PubMed]
  113. Ariotti, S.; Hogenbirk, M.A.; Dijkgraaf, F.E.; Visser, L.L.; Hoekstra, M.E.; Song, J.Y.; Jacobs, H.; Haanen, J.B.; Schumacher, T.N. T cell memory. Skin-resident memory CD8+ T cells trigger a state of tissue-wide pathogen alert. Science 2014, 346, 101–105. [Google Scholar] [CrossRef] [PubMed]
  114. Masopust, D.; Vezys, V.; Marzo, A.L.; Lefrancois, L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 2001, 291, 2413–2417. [Google Scholar] [CrossRef] [PubMed]
  115. Lefrancois, L.; Parker, C.M.; Olson, S.; Muller, W.; Wagner, N.; Schon, M.P.; Puddington, L. The role of beta7 integrins in CD8 T cell trafficking during an antiviral immune response. J. Exp. Med. 1999, 189, 1631–1638. [Google Scholar] [CrossRef] [PubMed]
  116. Johansson-Lindbom, B.; Svensson, M.; Wurbel, M.A.; Malissen, B.; Marquez, G.; Agace, W. Selective generation of gut tropic T cells in gut-associated lymphoid tissue (galt): Requirement for galt dendritic cells and adjuvant. J. Exp. Med. 2003, 198, 963–969. [Google Scholar] [CrossRef] [PubMed]
  117. Wiesel, M.; Oxenius, A. From crucial to negligible: Functional CD8+ T-cell responses and their dependence on CD4+ T-cell help. Eur. J. Immunol. 2012, 42, 1080–1088. [Google Scholar] [CrossRef] [PubMed]
  118. Marzo, A.L.; Vezys, V.; Klonowski, K.D.; Lee, S.J.; Muralimohan, G.; Moore, M.; Tough, D.F.; Lefrancois, L. Fully functional memory CD8 T cells in the absence of CD4 T cells. J. Immunol. 2004, 173, 969–975. [Google Scholar] [CrossRef] [PubMed]
  119. Sun, J.C.; Bevan, M.J. Defective CD8 T cell memory following acute infection without CD4 T cell help. Science 2003, 300, 339–342. [Google Scholar] [CrossRef] [PubMed]
  120. Sun, J.C.; Williams, M.A.; Bevan, M.J. Cd4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection. Nat. Immunol. 2004, 5, 927–933. [Google Scholar] [CrossRef] [PubMed]
  121. Shedlock, D.J.; Shen, H. Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 2003, 300, 337–339. [Google Scholar] [CrossRef] [PubMed]
  122. Shedlock, D.J.; Whitmire, J.K.; Tan, J.; MacDonald, A.S.; Ahmed, R.; Shen, H. Role of CD4 T cell help and costimulation in CD8 T cell responses during Listeria monocytogenes infection. J. Immunol. 2003, 170, 2053–2063. [Google Scholar] [CrossRef] [PubMed]
  123. Nakanishi, Y.; Lu, B.; Gerard, C.; Iwasaki, A. Cd8+ T lymphocyte mobilization to virus-infected tissue requires CD4+ T-cell help. Nature 2009, 462, 510–513. [Google Scholar] [CrossRef] [PubMed]
  124. Laidlaw, B.J.; Zhang, N.; Marshall, H.D.; Staron, M.M.; Guan, T.; Hu, Y.; Cauley, L.S.; Craft, J.; Kaech, S.M. Cd4+ T cell help guides formation of CD103+ lung-resident memory CD8+ T cells during influenza viral infection. Immunity 2014, 41, 633–645. [Google Scholar] [CrossRef] [PubMed]
  125. Sun, J.C.; Bevan, M.J. Cutting edge: Long-lived CD8 memory and protective immunity in the absence of CD40 expression on CD8 T cells. J. Immunol. 2004, 172, 3385–3389. [Google Scholar] [CrossRef] [PubMed]
  126. Hamilton, S.E.; Tvinnereim, A.R.; Harty, J.T. Listeria monocytogenes infection overcomes the requirement for CD40 ligand in exogenous antigen presentation to CD8+ T cells. J. Immunol. 2001, 167, 5603–5609. [Google Scholar] [CrossRef] [PubMed]
  127. Obar, J.J.; Molloy, M.J.; Jellison, E.R.; Stoklasek, T.A.; Zhang, W.; Usherwood, E.J.; Lefrancois, L. CD4+ T cell regulation of CD25 expression controls development of short-lived effector CD8+ T cells in primary and secondary responses. Proc. Natl. Acad. Sci. USA 2010, 107, 193–198. [Google Scholar] [CrossRef] [PubMed]
  128. Zenewicz, L.A.; Shen, H. Innate and adaptive immune responses to Listeria monocytogenes: A short overview. Microbes Infect. 2007, 9, 1208–1215. [Google Scholar] [CrossRef] [PubMed]
  129. Pamer, E.G.; Harty, J.T.; Bevan, M.J. Precise prediction of a dominant class i mhc-restricted epitope of Listeria monocytogenes. Nature 1991, 353, 852–855. [Google Scholar] [CrossRef] [PubMed]
  130. Pamer, E.G. Direct sequence identification and kinetic analysis of an MHC class I-restricted Listeria monocytogenes CTL epitope. J. Immunol. 1994, 152, 686–694. [Google Scholar] [PubMed]
  131. Harty, J.T.; Bevan, M.J. CD8+ T cells specific for a single nonamer epitope of Listeria monocytogenes are protective in vivo. J. Exp. Med. 1992, 175, 1531–1538. [Google Scholar] [CrossRef] [PubMed]
  132. Harty, J.T.; Pamer, E.G. CD8 T lymphocytes specific for the secreted p60 antigen protect against Listeria monocytogenes infection. J. Immunol. 1995, 154, 4642–4650. [Google Scholar] [PubMed]
  133. Harty, J.T.; Lenz, L.L.; Bevan, M.J. Primary and secondary immune responses to Listeria monocytogenes. Curr. Opin. Immunol. 1996, 8, 526–530. [Google Scholar] [CrossRef][Green Version]
  134. Hess, J.; Gentschev, I.; Miko, D.; Welzel, M.; Ladel, C.; Goebel, W.; Kaufmann, S.H. Superior efficacy of secreted over somatic antigen display in recombinant salmonella vaccine induced protection against listeriosis. Proc. Natl. Acad. Sci. USA 1996, 93, 1458–1463. [Google Scholar] [CrossRef] [PubMed]
  135. Shen, H.; Miller, J.F.; Fan, X.; Kolwyck, D.; Ahmed, R.; Harty, J.T. Compartmentalization of bacterial antigens: Differential effects on priming of CD8 T cells and protective immunity. Cell 1998, 92, 535–545. [Google Scholar] [CrossRef]
  136. Zenewicz, L.A.; Foulds, K.E.; Jiang, J.; Fan, X.; Shen, H. Nonsecreted bacterial proteins induce recall CD8 T cell responses but do not serve as protective antigens. J. Immunol. 2002, 169, 5805–5812. [Google Scholar] [CrossRef] [PubMed]
  137. Mora-Solano, C.; Wen, Y.; Han, H.; Chen, J.; Chong, A.S.; Miller, M.L.; Pompano, R.R.; Collier, J.H. Active immunotherapy for tnf-mediated inflammation using self-assembled peptide nanofibers. Biomaterials 2017, 149, 1–11. [Google Scholar] [CrossRef] [PubMed]
  138. Calderon-Gonzalez, R.; Frande-Cabanes, E.; Teran-Navarro, H.; Marimon, J.M.; Freire, J.; Salcines-Cuevas, D.; Carmen Farinas, M.; Onzalez-Rico, C.; Marradi, M.; Garcia, I.; et al. Gnp-gapdh1-22 nanovaccines prevent neonatal listeriosis by blocking microglial apoptosis and bacterial dissemination. Oncotarget 2017, 8, 53916–53934. [Google Scholar] [CrossRef] [PubMed]
  139. Wu, X.; Ju, X.; Du, L.; Yuan, J.; Wang, L.; He, R.; Chen, Z. Production of bacterial ghosts from gram-positive pathogen Listeria monocytogenes. Foodborne Pathog. Dis. 2017, 14, 1–7. [Google Scholar] [CrossRef] [PubMed]
  140. Torres, D.; Kohler, A.; Delbauve, S.; Caminschi, I.; Lahoud, M.H.; Shortman, K.; Flamand, V. IL-12p40/IL-10 producing preCD8α/Clec9A+ dendritic cells are induced in neonates upon Listeria monocytogenes infection. PLoS Pathog. 2016, 12, e1005561. [Google Scholar] [CrossRef] [PubMed]
  141. Ansari, M.A.; Zia, Q.; Kazmi, S.; Ahmad, E.; Azhar, A.; Johnson, K.E.; Zubair, S.; Owais, M. Efficacy of cell wall-deficient spheroplasts against experimental murine listeriosis. Scand. J. Immunol. 2015, 82, 10–24. [Google Scholar] [CrossRef] [PubMed]
  142. Rodriguez-Del Rio, E.; Marradi, M.; Calderon-Gonzalez, R.; Frande-Cabanes, E.; Penades, S.; Petrovsky, N.; Alvarez-Dominguez, C. A gold glyco-nanoparticle carrying a listeriolysin O peptide and formulated with advax delta inulin adjuvant induces robust T-cell protection against listeria infection. Vaccine 2015, 33, 1465–1473. [Google Scholar] [CrossRef] [PubMed]
  143. Clark, D.R.; Chaturvedi, V.; Kinder, J.M.; Jiang, T.T.; Xin, L.; Ertelt, J.M.; Way, S.S. Perinatal Listeria monocytogenes susceptibility despite preconceptual priming and maintenance of pathogen-specific CD8+ T cells during pregnancy. Cell. Mol. Immunol. 2014, 11, 595–605. [Google Scholar] [CrossRef] [PubMed]
  144. Kono, M.; Nakamura, Y.; Suda, T.; Uchijima, M.; Tsujimura, K.; Nagata, T.; Giermasz, A.S.; Kalinski, P.; Nakamura, H.; Chida, K. Enhancement of protective immunity against intracellular bacteria using type-1 polarized dendritic cell (DC) vaccine. Vaccine 2012, 30, 2633–2639. [Google Scholar] [CrossRef] [PubMed]
  145. Masopust, D.; Vezys, V.; Wherry, E.J.; Barber, D.L.; Ahmed, R. Cutting edge: Gut microenvironment promotes differentiation of a unique memory CD8 T cell population. J. Immunol. 2006, 176, 2079–2083. [Google Scholar] [CrossRef] [PubMed]
  146. Masopust, D.; Ha, S.J.; Vezys, V.; Ahmed, R. Stimulation history dictates memory CD8 T cell phenotype: Implications for prime-boost vaccination. J. Immunol. 2006, 177, 831–839. [Google Scholar] [CrossRef] [PubMed]
  147. Schenkel, J.M.; Fraser, K.A.; Casey, K.A.; Beura, L.K.; Pauken, K.E.; Vezys, V.; Masopust, D. IL-15-independent maintenance of tissue-resident and boosted effector memory CD8 T cells. J. Immunol. 2016, 196, 3920–3926. [Google Scholar] [CrossRef] [PubMed]
  148. Shin, H.; Iwasaki, A. A vaccine strategy that protects against genital herpes by establishing local memory T cells. Nature 2012, 491, 463–467. [Google Scholar] [CrossRef] [PubMed][Green Version]
  149. Lecuit, M.; Nelson, D.M.; Smith, S.D.; Khun, H.; Huerre, M.; Vacher-Lavenu, M.C.; Gordon, J.I.; Cossart, P. Targeting and crossing of the human maternofetal barrier by Listeria monocytogenes: Role of internalin interaction with trophoblast e-cadherin. Proc. Natl. Acad. Sci. USA 2004, 101, 6152–6157. [Google Scholar] [CrossRef] [PubMed]
  150. Chaturvedi, V.; Ertelt, J.M.; Jiang, T.T.; Kinder, J.M.; Xin, L.; Owens, K.J.; Jones, H.N.; Way, S.S. CXCR3 blockade protects against Listeria monocytogenes infection-induced fetal wastage. J. Clin. Investig. 2015, 125, 1713–1725. [Google Scholar] [CrossRef] [PubMed]
  151. Pamer, E.G.; Wang, C.R.; Flaherty, L.; Lindahl, K.F.; Bevan, M.J. H-2M3 presents a Listeria monocytogenes peptide to cytotoxic T lymphocytes. Cell 1992, 70, 215–223. [Google Scholar] [CrossRef]
  152. Kurlander, R.J.; Shawar, S.M.; Brown, M.L.; Rich, R.R. Specialized role for a murine class i-b MHC molecule in prokaryotic host defenses. Science 1992, 257, 678–679. [Google Scholar] [CrossRef] [PubMed]
  153. Lenz, L.L.; Dere, B.; Bevan, M.J. Identification of an H2-M3-restricted listeria epitope: Implications for antigen presentation by M3. Immunity 1996, 5, 63–72. [Google Scholar] [CrossRef]
  154. Princiotta, M.F.; Lenz, L.L.; Bevan, M.J.; Staerz, U.D. H2-M3 restricted presentation of a listeria-derived leader peptide. J. Exp. Med. 1998, 187, 1711–1719. [Google Scholar] [CrossRef] [PubMed]
  155. Gulden, P.H.; Fischer, P., 3rd; Sherman, N.E.; Wang, W.; Engelhard, V.H.; Shabanowitz, J.; Hunt, D.F.; Pamer, E.G. A Listeria monocytogenes pentapeptide is presented to cytolytic T lymphocytes by the H2-M3 mhc class ib molecule. Immunity 1996, 5, 73–79. [Google Scholar] [CrossRef]
  156. Kerksiek, K.M.; Busch, D.H.; Pamer, E.G. Variable immunodominance hierarchies for H2-M3-restricted n-formyl peptides following bacterial infection. J. Immunol. 2001, 166, 1132–1140. [Google Scholar] [CrossRef] [PubMed]
  157. Ploss, A.; Lauvau, G.; Contos, B.; Kerksiek, K.M.; Guirnalda, P.D.; Leiner, I.; Lenz, L.L.; Bevan, M.J.; Pamer, E.G. Promiscuity of mhc class ib-restricted T cell responses. J. Immunol. 2003, 171, 5948–5955. [Google Scholar] [CrossRef] [PubMed]
  158. D’Orazio, S.E.; Velasquez, M.; Roan, N.R.; Naveiras-Torres, O.; Starnbach, M.N. The Listeria monocytogenes lema gene product is not required for intracellular infection or to activate fmigwii-specific T cells. Infect. Immun. 2003, 71, 6721–6727. [Google Scholar] [CrossRef] [PubMed]
  159. Ploss, A.; Tran, A.; Menet, E.; Leiner, I.; Pamer, E.G. Cross-recognition of n-formylmethionine peptides is a general characteristic of H2-M3-restricted CD8+ T cells. Infect. Immun. 2005, 73, 4423–4426. [Google Scholar] [CrossRef] [PubMed]
  160. Seaman, M.S.; Wang, C.R.; Forman, J. MHC class ib-restricted CTL provide protection against primary and secondary Listeria monocytogenes infection. J. Immunol. 2000, 165, 5192–5201. [Google Scholar] [CrossRef] [PubMed]
  161. Kerksiek, K.M.; Busch, D.H.; Pilip, I.M.; Allen, S.E.; Pamer, E.G. H2-M3-restricted T cells in bacterial infection: Rapid primary but diminished memory responses. J. Exp. Med. 1999, 190, 195–204. [Google Scholar] [CrossRef] [PubMed]
  162. Xu, H.; Chun, T.; Choi, H.J.; Wang, B.; Wang, C.R. Impaired response to listeria in H2-M3-deficient mice reveals a nonredundant role of MHC class ib-specific T cells in host defense. J. Exp. Med. 2006, 203, 449–459. [Google Scholar] [CrossRef] [PubMed]
  163. Kerksiek, K.M.; Ploss, A.; Leiner, I.; Busch, D.H.; Pamer, E.G. H2-m3-restricted memory T cells: Persistence and activation without expansion. J. Immunol. 2003, 170, 1862–1869. [Google Scholar] [CrossRef] [PubMed]
  164. Hamilton, S.E.; Porter, B.B.; Messingham, K.A.; Badovinac, V.P.; Harty, J.T. Mhc class IA-restricted memory T cells inhibit expansion of a nonprotective mhc class ib (H2-M3)-restricted memory response. Nat. Immunol. 2004, 5, 159–168. [Google Scholar] [CrossRef] [PubMed]
  165. Rothman, J.; Paterson, Y. Live-attenuated listeria-based immunotherapy. Expert Rev. Vaccines 2013, 12, 493–504. [Google Scholar] [CrossRef] [PubMed]
  166. Wood, L.M.; Paterson, Y. Attenuated Listeria monocytogenes: A powerful and versatile vector for the future of tumor immunotherapy. Front. Cell. Infect. Microbiol. 2014, 4, 51. [Google Scholar] [CrossRef] [PubMed]
  167. Yu, Y.A.; Shabahang, S.; Timiryasova, T.M.; Zhang, Q.; Beltz, R.; Gentschev, I.; Goebel, W.; Szalay, A.A. Visualization of tumors and metastases in live animals with bacteria and vaccinia virus encoding light-emitting proteins. Nat. Biotechnol. 2004, 22, 313–320. [Google Scholar] [CrossRef] [PubMed]
  168. Kim, S.H.; Castro, F.; Paterson, Y.; Gravekamp, C. High efficacy of a listeria-based vaccine against metastatic breast cancer reveals a dual mode of action. Cancer Res. 2009, 69, 5860–5866. [Google Scholar] [CrossRef] [PubMed]
  169. Quispe-Tintaya, W.; Chandra, D.; Jahangir, A.; Harris, M.; Casadevall, A.; Dadachova, E.; Gravekamp, C. Nontoxic radioactive listeriaat is a highly effective therapy against metastatic pancreatic cancer. Proc. Natl. Acad. Sci. USA 2013, 110, 8668–8673. [Google Scholar] [CrossRef] [PubMed]
  170. Finelli, A.; Kerksiek, K.M.; Allen, S.E.; Marshall, N.; Mercado, R.; Pilip, I.; Busch, D.H.; Pamer, E.G. Mhc class I restricted T cell responses to Listeria monocytogenes, an intracellular bacterial pathogen. Immunol. Res. 1999, 19, 211–223. [Google Scholar] [CrossRef] [PubMed]
  171. Wolf, B.J.; Princiotta, M.F. Processing of recombinant Listeria monocytogenes proteins for mhc class I presentation follows a dedicated, high-efficiency pathway. J. Immunol. 2013, 190, 2501–2509. [Google Scholar] [CrossRef] [PubMed]
  172. Souders, N.C.; Sewell, D.A.; Pan, Z.K.; Hussain, S.F.; Rodriguez, A.; Wallecha, A.; Paterson, Y. Listeria-based vaccines can overcome tolerance by expanding low avidity CD8+ T cells capable of eradicating a solid tumor in a transgenic mouse model of cancer. Cancer Immun. 2007, 7, 2. [Google Scholar] [PubMed]
  173. Sewell, D.A.; Pan, Z.K.; Paterson, Y. Listeria-based HPV-16 E7 vaccines limit autochthonous tumor growth in a transgenic mouse model for HPV-16 transformed tumors. Vaccine 2008, 26, 5315–5320. [Google Scholar] [CrossRef] [PubMed][Green Version]
  174. Hussain, S.F.; Paterson, Y. CD4+CD25+ regulatory T cells that secrete tgfbeta and IL-10 are preferentially induced by a vaccine vector. J. Immunother. 2004, 27, 339–346. [Google Scholar] [CrossRef] [PubMed]
  175. Wallecha, A.; Singh, R.; Malinina, I. Listeria monocytogenes (Lm)-LLO immunotherapies reduce the immunosuppressive activity of myeloid-derived suppressor cells and regulatory T cells in the tumor microenvironment. J. Immunother. 2013, 36, 468–476. [Google Scholar] [CrossRef] [PubMed]
  176. Mkrtichyan, M.; Chong, N.; Abu Eid, R.; Wallecha, A.; Singh, R.; Rothman, J.; Khleif, S.N. Anti-pd-1 antibody significantly increases therapeutic efficacy of Listeria monocytogenes (Lm)-LLO immunotherapy. J. Immunother. Cancer 2013, 1, 15. [Google Scholar] [CrossRef] [PubMed]
  177. Guirnalda, P.; Wood, L.; Goenka, R.; Crespo, J.; Paterson, Y. Interferon gamma-induced intratumoral expression of cxcl9 alters the local distribution of T cells following immunotherapy with Listeria monocytogenes. Oncoimmunology 2013, 2, e25752. [Google Scholar] [CrossRef] [PubMed]
  178. Paterson, Y.; Johnson, R.S. Progress towards the use of Listeria monocytogenes as a live bacterial vaccine vector for the delivery of HIV antigens. Expert Rev. Vaccines 2004, 3, S119–S134. [Google Scholar] [CrossRef] [PubMed]
  179. Cory, L.; Chu, C. ADXS-HPV: A therapeutic listeria vaccination targeting cervical cancers expressing the HPV E7 antigen. Hum. Vaccines Immunother. 2014, 10, 3190–3195. [Google Scholar] [CrossRef] [PubMed]
  180. Le, D.T.; Brockstedt, D.G.; Nir-Paz, R.; Hampl, J.; Mathur, S.; Nemunaitis, J.; Sterman, D.H.; Hassan, R.; Lutz, E.; Moyer, B.; et al. A live-attenuated listeria vaccine (ANZ-100) and a live-attenuated listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: Phase i studies of safety and immune induction. Clin. Cancer Res. 2012, 18, 858–868. [Google Scholar] [CrossRef] [PubMed]
  181. Le, D.T.; Wang-Gillam, A.; Picozzi, V.; Greten, T.F.; Crocenzi, T.; Springett, G.; Morse, M.; Zeh, H.; Cohen, D.; Fine, R.L.; et al. Safety and survival with gvax pancreas prime and Listeria monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J. Clin. Oncol. 2015, 33, 1325–1333. [Google Scholar] [CrossRef] [PubMed]
  182. Maciag, P.C.; Radulovic, S.; Rothman, J. The first clinical use of a live-attenuated Listeria monocytogenes vaccine: A phase I safety study of LM-LLO-E7 in patients with advanced carcinoma of the cervix. Vaccine 2009, 27, 3975–3983. [Google Scholar] [CrossRef] [PubMed]
  183. Mason, N.J.; Gnanandarajah, J.S.; Engiles, J.B.; Gray, F.; Laughlin, D.; Gaurnier-Hausser, A.; Wallecha, A.; Huebner, M.; Paterson, Y. Immunotherapy with a her2-targeting listeria induces her2-specific immunity and demonstrates potential therapeutic effects in a phase I trial in canine osteosarcoma. Clin. Cancer Res. 2016, 22, 4380–4390. [Google Scholar] [CrossRef] [PubMed]
  184. Pages, F.; Galon, J.; Dieu-Nosjean, M.C.; Tartour, E.; Sautes-Fridman, C.; Fridman, W.H. Immune infiltration in human tumors: A prognostic factor that should not be ignored. Oncogene 2010, 29, 1093–1102. [Google Scholar] [CrossRef] [PubMed]
  185. Gooden, M.J.; de Bock, G.H.; Leffers, N.; Daemen, T.; Nijman, H.W. The prognostic influence of tumour-infiltrating lymphocytes in cancer: A systematic review with meta-analysis. Br. J. Cancer 2011, 105, 93–103. [Google Scholar] [CrossRef] [PubMed]
  186. Qiu, Z.; Huang, H.; Grenier, J.M.; Perez, O.A.; Smilowitz, H.M.; Adler, B.; Khanna, K.M. Cytomegalovirus-based vaccine expressing a modified tumor antigen induces potent tumor-specific CD8+ T-cell response and protects mice from melanoma. Cancer Immunol. Res. 2015, 3, 536–546. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Schematic for the CD8 T cell response to Lm infection. The CD8 T cell response to Listeria monocytogenes (Lm) infection can be characterized by several major phases: (1) priming and activation; (2) clonal expansion and differentiation; (3) contraction; and (4) memory. Dendritic cells (DC) acquire Lm and present antigen to naïve CD8 T cells to activate them. Activated CD8 T cells subsequently undergo clonal expansion and differentiation. CD8 T cells first differentiate into early effector cells (EEC), which may become short-lived effector cells (SLEC) or memory precursor effector cells (MPEC). Following the peak of clonal expansion and pathogen clearance, the majority of effector CD8 T cells die during contraction. The remaining effector cells survive to form a long-lived memory population that can provide protection to subsequent challenges. During expansion and differentiation, effector CD8 T cells migrate to the intestine where they form resident memory CD8 T cells. Effector CD8 T cells differentiate mostly into SLEC in the spleen, while they are skewed towards EEC and MPEC in the intestine. The magnitude and differentiation pattern of effector CD8 T cells in the intestine differ after intravenous (i.v.) and oral Lm infection.
Figure 1. Schematic for the CD8 T cell response to Lm infection. The CD8 T cell response to Listeria monocytogenes (Lm) infection can be characterized by several major phases: (1) priming and activation; (2) clonal expansion and differentiation; (3) contraction; and (4) memory. Dendritic cells (DC) acquire Lm and present antigen to naïve CD8 T cells to activate them. Activated CD8 T cells subsequently undergo clonal expansion and differentiation. CD8 T cells first differentiate into early effector cells (EEC), which may become short-lived effector cells (SLEC) or memory precursor effector cells (MPEC). Following the peak of clonal expansion and pathogen clearance, the majority of effector CD8 T cells die during contraction. The remaining effector cells survive to form a long-lived memory population that can provide protection to subsequent challenges. During expansion and differentiation, effector CD8 T cells migrate to the intestine where they form resident memory CD8 T cells. Effector CD8 T cells differentiate mostly into SLEC in the spleen, while they are skewed towards EEC and MPEC in the intestine. The magnitude and differentiation pattern of effector CD8 T cells in the intestine differ after intravenous (i.v.) and oral Lm infection.
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