Search Results (108)

Background/Objectives: Organ transplantation is a life-saving intervention for patients with terminal organ failure, but long-term success is hindered by graft rejection and dependence on lifelong immunosuppressants. These drugs pose risks such as opportunistic infections and malignancies. Chimeric antigen receptor (CAR) technology, originally developed for cancer immunotherapy, has been adapted to regulatory T cells (Tregs) to enhance their antigen-specific immunosuppressive function. This systematic review evaluates the preclinical development of CAR-Tregs in promoting graft tolerance and suppressing graft-versus-host disease (GvHD). Methods: A systematic review following PROSPERO guidelines (CRD420251073207) was conducted across PubMed, Scopus, and Web of Science for studies published from 2015 to 2024. After screening 105 articles, 17 studies involving CAR-Tregs in preclinical or in vivo transplant or GvHD models were included. Results: CAR-Tregs exhibited superior graft-protective properties compared to unmodified or polyclonal Tregs. HLA-A2-specific CAR-Tregs consistently improved graft survival, reduced inflammatory cytokines, and suppressed immune cell infiltration across skin, heart, and pancreatic islet transplant models. The inclusion of CD28 as a co-stimulatory domain enhanced Treg function and FOXP3 expression. However, challenges such as Treg exhaustion, tonic signaling, and reduced in vivo persistence were noted. Some studies reported synergistic effects when CAR-Tregs were combined with immunosuppressants like rapamycin or tacrolimus. Conclusions: CAR-Tregs offer a promising strategy for inducing targeted immunosuppression in allogeneic transplantation. While preclinical findings are encouraging, further work is needed to optimize CAR design, ensure in vivo stability, and establish clinical-scale manufacturing before translation to human trials. Full article

CD137 is a prominent costimulatory molecule of the tumor necrosis factor (TNF) receptor superfamily that activates T cells through a complex bidirectional signaling process involving CD137L. The clinical value of immunotherapies underscores the potential of CD137L/CD137 as an effective target for boosting antitumor immune responses; however, the intricate mechanisms governing these interactions have not been fully elucidated. Herein, we constructed various oligomeric states of CD137L (monomeric, dimeric, and trimeric CD137L) and explored their interactions with CD137 using molecular dynamics simulations. Our findings revealed that trimeric CD137L exhibits higher thermal stability but reduced binding affinity for CD137 compared with the dimer form, with the A’B’ loop of CD137L playing a critical role in both structural stability and promoting CD137 interactions. Notably, the formation of hexameric structures enhanced the binding affinity and stability. This study provides valuable insights into the CD137L/CD137 bidirectional signaling mechanisms, which may inform the design of next-generation CD137 agonists. Ultimately, these advancements may improve cancer immunotherapy strategies, aiming to enhance therapeutic outcomes for patients through more effective and targeted therapies. Full article

Class IA PI3K p110δ and p110α subunits participate in TCR and costimulatory receptor signals involved in T cell-mediated immunity, but the role of p110α is not completely understood. Here, we analyzed a mouse model of the Cre-dependent functional inactivation of p110α (kinase dead) in T lymphocytes (p110αKD-T, KD). KD mice showed increased cellularity in thymus and spleen and altered T cell differentiation with increased number of CD4⁺CD8⁺ DP thymocytes, enhanced proportion of CD4⁺ SP lymphocytes linked to altered apoptosis, lower Treg cells, and increased AKT and ERK phosphorylation in activated thymocytes. In the spleen, the percentages of CD4⁺ Treg cells and CD8⁺ naive lymphocytes were reduced. In vitro, the differentiation of CD4⁺ cells from p110αKD-T mice showed lower induced Treg (iTreg) cell yield or IL-10 secretion. Moreover, Tfh cell yield, IL-21 secretion, and PI3-K-dependent elongation were hampered, as was Erk and Akt activation. Th1 or Th17 differentiation in vitro was not altered. The immunization of p110α-KD-T mice with KLH protein antigen induced an enhanced proportion of CXCR5⁺ CD4⁺ cells and germinal center B cells, increased ICOS expression in CD4⁺ cells, or IFN-γ secretion upon antigen re-activation in vitro. However, anti-KLH antibody responses in serum was similar in WT or p110α KD mice. These data show that T cell-specific p110α inactivation alters T cell differentiation and function. Full article

Metabolite accumulation in the tumor microenvironment fosters immune evasion and limits the efficiency of immunotherapeutic approaches. Methylthioadenosine phosphorylase (MTAP), which catalyzes the degradation of 5′-deoxy-5′methylthioadenosine (MTA), is downregulated in many cancer entities. Consequently, MTA accumulates in the microenvironment of MTAP-deficient tumors, where it is known to inhibit tumor-infiltrating T cells and NK cells. However, the impact of MTA on other intra-tumoral immune cells has not yet been fully elucidated. To study the effects of MTA on dendritic cells (DCs), human monocytes were maturated into DCs with (MTA-DC) or without MTA (co-DC) and analyzed for activation, differentiation, and T cell-stimulating capacity. MTA altered the cytokine secretion profile of monocytes and impaired their maturation into dendritic cells. MTA-DCs produced less IL-12 and showed a more immature-like phenotype characterized by decreased expression of the co-stimulatory molecules CD80, CD83, and CD86 and increased expression of the monocyte markers CD14 and CD16. Consequently, MTA reduced the capability of DCs to stimulate T cells. Mechanistically, the MTA-induced effects on monocytes and DCs were mediated by a mechanism beyond adenosine receptor signaling. These results provide new insights into how altered polyamine metabolism impairs the maturation of monocyte-derived DCs and impacts the crosstalk between T and dendritic cells. Full article

Sepsis pathophysiology involves a dysregulated immune response to infection, excessive inflammation, and immune paralysis. This study explores the relationships between cell death biomarkers (serum-soluble levels of programmed cell death protein 1 (PD-1), programmed death ligand 1 (PD-L1), and interleukin-7 (IL-7)) and the percentages of various lymphocyte subsets in relation to the severity and progression of sepsis. This prospective, observational study included 87 critically ill patients. We monitored parameters on days 1 (sepsis was diagnosed according to the Sepsis-3 Consensus) and 5. We established an IL-7 cutoff value of 1.94 pg/mL by comparing levels between a healthy control group and patients with sepsis (p < 0.0001). Lymphopenia was observed in all patients, with negative correlations between helper T lymphocytes and cytotoxic and B lymphocytes, and positive correlations involving cytotoxic lymphocytes across all groups. We found correlations between PD-1/PD-L1 and lymphocyte subsets. IL-7 showed a statistical correlation with PD-1 in non-survivors. Assessing lymphocyte levels shows potential as a biomarker for evaluating the progression of sepsis. Monitoring IL-7 levels could help assess survival, as low levels are associated with higher mortality risk. Monitoring IL-7 levels could help assess survival, as low levels are associated with higher mortality risk. Elevated PD-1/PD-L1 expression impairs costimulatory signalling, reducing T cell responses and lymphopenia, which increases the risk of nosocomial infections. Full article

Background: FMS-like tyrosine kinase 3 (FLT3) mutations or internal tandem duplication occur in 30% of acute myeloid leukemia (AML) cases. In these cases, FLT3 inhibitors (FLT3i) are approved for induction treatment and relapse. Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the recommended post-induction therapy for suitable patients. However, the role of FLT3i therapy after alloHSCT remains unclear. Therefore, we investigated the three currently available FLT3i, gilteritinib, midostaurin, and quizartinib, in terms of their immunosuppressive effect on dendritic cells (DCs). DCs are professional antigen-presenting cells inducing T-cell responses to infectious stimuli. Highly activated DCs can also cause complications after alloHSCT, such as triggering Graft versus Host disease, a serious and potentially life-threatening complication after alloHSCT. Methods: To study the immunomodulatory effects on DCs, we differentiated murine and human DCs in the presence of FLT3i and performed immunophenotyping by flow cytometry and cytokine measurements and investigated gene and protein expression. Results: We detected a dose-dependent immunosuppressive effect of midostaurin, which decreased the expression of costimulatory markers like CD86, and found a reduced secretion of pro-inflammatory cytokines such as IL-12, TNFα, and IL-6. Mechanistically, we show that midostaurin inhibits TLR and TNF signaling and NFκB, PI3K, and MAPK pathways. The immunosuppressive effect of gilteritinib was less pronounced, while quizartinib did not show truncation of relevant signaling pathways. Conclusions: Our results suggest different immunosuppressive effects of these three FLT3i and may, therefore, provide an additional rationale for optimal maintenance therapy after alloHSCT of FLT3-positive AML patients to prevent infectious complications and GvHD mediated by DCs. Full article

Common variable immunodeficiency (CVID) is the most common symptomatic antibody deficiency, characterized by heterogeneous genetic, immunological, and clinical phenotypes. It is no longer conceived as a sole disease but as an umbrella diagnosis comprising a spectrum of clinical conditions, with defects in antibody biosynthesis as their common denominator and complex pathways determining B and T cell developmental impairments due to genetic defects of many receptors and ligands, activating and co-stimulatory molecules, and intracellular signaling molecules. Consequently, these genetic variants may affect crucial immunological processes of antigen presentation, antibody class switch recombination, antibody affinity maturation, and somatic hypermutation. While infections are the most common features of pediatric CVID, variants in genes linked to antibody production defects play a role in pathomechanisms of immune dysregulation with autoimmunity, allergy, and lymphoproliferation reflecting the diversity of the immunogenetic underpinnings of CVID. Herein, we have reviewed the aspects of genetics in CVID, including the monogenic, digenic, and polygenic models of inheritance exemplified by a spectrum of genes relevant to CVID pathophysiology. We have also briefly discussed the epigenetic mechanisms associated with micro RNA, DNA methylation, chromatin reorganization, and histone protein modification processes as background for CVID development. Full article

Improving chimeric antigen receptor (CAR)-T cell therapeutic outcomes and expanding its applicability to solid tumors requires further refinement of CAR-T cells. We previously reported that CAR-T cells bearing a herpes virus entry mediator (HVEM)-derived co-stimulatory signal domain (CSSD) (HVEM-CAR-T cells) exhibit superior functions and characteristics. Here, we conducted comparative analyses to evaluate the impact of different CSSDs on CAR-T cell exhaustion. The results indicated that HVEM-CAR-T cells had significantly lower frequencies of exhausted cells and exhibited the highest proliferation rates upon antigenic stimulation. Furthermore, proliferation inhibition by programmed cell death ligand 1 was stronger in CAR-T cells bearing CD28-derived CSSD (CD28-CAR-T cells) whereas it was weaker in HVEM-CAR-T. Additionally, HVEM-CAR-T cells maintained a low exhaustion level even after antigen-dependent proliferation and exhibited potent killing activities, suggesting that HVEM-CAR-T cells might be less prone to early exhaustion. Analysis of CAR localization on the cell surface revealed that CAR formed clusters in CD28-CAR-T cells whereas uniformly distributed in HVEM-CAR-T cells. Analysis of CD3ζ phosphorylation indicated that CAR-dependent tonic signals were strongly sustained in CD28-CAR-T cells whereas they were significantly weaker in HVEM-CAR-T cells. Collectively, these results suggest that the HVEM-derived CSSD is useful for generating CAR-T cells with exhaustion-resistant properties, which could be effective against solid tumors. Full article

Background and Objectives: Sepsis involves a dysregulated host response, characterized by simultaneous immunosuppression and hyperinflammation. Initially, there is the release of pro-inflammatory factors and immune system dysfunction, followed by persistent immune paralysis leading to apoptosis. This study investigates sepsis-induced apoptosis and its pathways, by assessing changes in PD-1 and PD-L1 serum levels, CD4+ and CD8+ T cells, and Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation (APACHE II) severity scores. Materials and Methods: This prospective, observational, single-centre study enrolled 87 sepsis patients admitted to the intensive care unit at the County Emergency Clinical Hospital in Târgu Mureș, Romania. We monitored the parameters on day 1 (the day sepsis or septic shock was diagnosed as per the Sepsis-3 Consensus) and day 5. Results: Our study found a statistically significant variation in the SOFA score for the entirety of the patients between the studied days (p = 0.001), as well as for the studied patient groups: sepsis, septic shock, survivors, and non-survivors (p = 0.001, p = 0.003, p = 0.01, p = 0.03). On day 1, we found statistically significant correlations between CD8+ cells and PD-1 (p = 0.02) and PD-L1 (p = 0.04), CD4+ and CD8+ cells (p < 0.0001), SOFA and APACHE II scores (p < 0.0001), and SOFA and APACHE II scores and PD-L1 (p = 0.001 and p = 0.01). On day 5, we found statistically significant correlations between CD4+ and CD8+ cells and PD-L1 (p = 0.03 and p = 0.0099), CD4+ and CD8+ cells (p < 0.0001), and SOFA and APACHE II scores (p < 0.0001). Conclusions: The reduction in Th CD4+ and Tc CD8+ lymphocyte subpopulations were evident from day 1, indicating that apoptosis is a crucial factor in the progression of sepsis and septic shock. The increased expression of the PD-1/PD-L1 axis impairs costimulatory signalling, leading to diminished T cell responses and lymphopenia, thereby increasing the susceptibility to nosocomial infections. Full article

Takayasu’s arteritis (TAK) manifests as an insidiously progressive and debilitating form of granulomatous inflammation including the aorta and its major branches. The precise etiology of TAK remains elusive, with current understanding suggesting an autoimmune origin primarily driven by T cells. Notably, a growing body of evidence bears testimony to the widespread effects of B cells on disease pathogenesis and progression. Distinct alterations in peripheral B cell subsets have been described in individuals with TAK. Advancements in technology have facilitated the identification of novel autoantibodies in TAK. Moreover, emerging data suggest that dysregulated signaling cascades downstream of B cell receptor families, including interactions with innate pattern recognition receptors such as toll-like receptors, as well as co-stimulatory molecules like CD40, CD80 and CD86, may result in the selection and proliferation of autoreactive B cell clones in TAK. Additionally, ectopic lymphoid neogenesis within the aortic wall of TAK patients exhibits functional characteristics. In recent decades, therapeutic interventions targeting B cells, notably utilizing the anti-CD20 monoclonal antibody rituximab, have demonstrated efficacy in TAK. Despite the importance of the humoral immune response, a systematic understanding of how autoreactive B cells contribute to the pathogenic process is still lacking. This review provides a comprehensive overview of the biological significance of B cell-mediated autoimmunity in TAK pathogenesis, as well as insights into therapeutic strategies targeting the humoral response. Furthermore, it examines the roles of T-helper and T follicular helper cells in humoral immunity and their potential contributions to disease mechanisms. We believe that further identification of the pathogenic role of autoimmune B cells and the underlying regulation system will lead to deeper personalized management of TAK patients. We believe that further elucidation of the pathogenic role of autoimmune B cells and the underlying regulatory mechanisms holds promise for the development of personalized approaches to managing TAK patients. Full article

Dendritic cells (DCs) can initiate immune response through the presenting antigens to naïve T lymphocytes. Esculeoside A (EsA), a spirosolane glycoside, is reported as a major component in the ripe fruit of tomato. Little is known about the effect of tomato saponin on mice bone marrow-derived DCs. This study revealed that EsA and its aglycon, esculeogenin A (Esg-A), attenuated the phenotypic and functional maturation of murine DCs stimulated by lipopolysaccharide (LPS). We found that EsA/Esg-A down-regulated the expression of major histocompatibility complex type II molecules and costimulatory molecule CD86 after LPS stimulation. It was also determined that EsA-/Esg-A-treated DCs were poor stimulators of allogeneic T-cell proliferation and exhibited impaired interleukin-12 and TNF-α production. Additionally, EsA/Esg-A was able to inhibit TLR4-related and p-NFκB signaling pathways. This study shows new insights into the immunopharmacology of EsA/Esg-A, and represents a novel approach to controlling DCs for therapeutic application. Full article

Zinc is an essential trace element that plays a crucial role in T cell immunity. During T cell activation, zinc is not only structurally important, but zinc signals can also act as a second messenger. This research investigates zinc signals in T cell activation and their function in T helper cell 1 differentiation. For this purpose, peripheral blood mononuclear cells were activated via the T cell receptor-CD3 complex, and via CD28 as a costimulatory signal. Fast and long-term changes in intracellular zinc and calcium were monitored by flow cytometry. Further, interferon (IFN)-γ was analyzed to investigate the differentiation into T helper 1 cells. We show that fast zinc fluxes are induced via CD3. Also, the intracellular zinc concentration dramatically increases 72 h after anti-CD3 and anti-CD28 stimulation, which goes along with the high release of IFN-γ. Interestingly, we found that zinc signals can function as a costimulatory signal for T helper cell 1 differentiation when T cells are activated only via CD3. These results demonstrate the importance of zinc signaling alongside calcium signaling in T cell differentiation. Full article

The transmembrane glycoprotein OX40 receptor (OX40) and its ligand, OX40L, are instrumental modulators of the adaptive immune response in humans. OX40 functions as a costimulatory molecule that promotes T cell activation, differentiation, and survival through ligation with OX40L. T cells play an integral role in the pathogenesis of several inflammatory skin conditions, including atopic dermatitis (AD). In particular, T helper 2 (T_H2) cells strongly contribute to AD pathogenesis via the production of cytokines associated with type 2 inflammation (e.g., IL-4, IL-5, IL-13, and IL-31) that lead to skin barrier dysfunction and pruritus. The OX40-OX40L interaction also promotes the activation and proliferation of other T helper cell populations (e.g., T_H1, T_H22, and T_H17), and AD patients have demonstrated higher levels of OX40 expression on peripheral blood mononuclear cells than healthy controls. As such, the OX40-OX40L pathway is a potential target for AD treatment. Novel therapies targeting the OX40 pathway are currently in development, several of which have demonstrated promising safety and efficacy results in patients with moderate-to-severe AD. Herein, we review the function of OX40 and the OX40-OX40L signaling pathway, their role in AD pathogenesis, and emerging therapies targeting OX40-OX40L that may offer insights into the future of AD management. Full article

The field of transplantation, including the specialized area of vascularized composite allotransplantation (VCA), has been transformed since the first hand transplant in 1998. The major challenge in VCA comes from the need for life-long immunosuppressive therapy due to its non-vital nature and a high rate of systemic complications. Ongoing research is focused on immunosuppressive therapeutic strategies to avoid toxicity and promote donor-specific tolerance. This includes studying the balance between tolerance and effector mechanisms in immune modulation, particularly the role of costimulatory signals in T lymphocyte activation. Costimulatory signals during T cell activation can have either stimulatory or inhibitory effects. Interfering with T cell activation through costimulation blockade strategies shows potential in avoiding rejection and prolonging the survival of transplanted organs. This review paper aims to summarize current data on the immunologic role of costimulatory blockade in the field of transplantation. It focuses on strategies that can be applied in vascularized composite allotransplantation, offering insights into novel methods for enhancing the success and safety of these procedures. Full article

The combination of signals from the T-cell receptor (TCR) and co-stimulatory molecules triggers transcriptional programs that lead to proliferation, cytokine secretion, and effector functions. We compared the impact of engaging the TCR with CD28 and/or CD43 at different time points relative to TCR engagement on T-cell function. TCR and CD43 simultaneous engagement resulted in higher CD69 and PD-1 expression levels than in TCR and CD28-stimulated cells, with a cytokine signature of mostly effector, inflammatory, and regulatory cytokines, while TCR and CD28-activated cells secreted all categories of cytokines, including stimulatory cytokines. Furthermore, the timing of CD43 engagement relative to TCR ligation, and to a lesser degree that of CD28, resulted in distinct patterns of expression of cytokines, chemokines, and growth factors. Complete cell activation was observed when CD28 or CD43 were engaged simultaneously with or before the TCR, but ligating the TCR before CD43 or CD28 failed to complete a cell activation program regarding cytokine secretion. As the order in which CD43 or CD28 and the TCR were engaged resulted in different combinations of cytokines that shape distinct T-cell immune programs, we analyzed their upstream sequences to assess whether the combinations of cytokines were associated with different sets of regulatory elements. We found that the order in which the TCR and CD28 or CD43 are engaged predicts the recruitment of specific sets of chromatin remodelers and TFSS, which ultimately regulate T-cell polarization and plasticity. Our data underscore that the combination of co-stimulatory molecules and the time when they are engaged relative to the TCR can change the cell differentiation program. Full article