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Tissue-Resident Memory T Cells

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (15 July 2021) | Viewed by 48520

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Dr. Jörg Hamann

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Guest Editor

1. Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands
2. Department of Neuroimmunology, Netherlands Institute for Neuroscience, Meibergdreef 47, 1105BA Amsterdam, The Netherlands
Interests: immune cells of the human brain; neuroinflammation; leukocyte surface markers

Dr. Klaas van Gisbergen

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Guest Editor

1. Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Center, Plesmanlaan 125, 1066CX Amsterdam, The Netherlands
2. Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands
Interests: memory CD8 T-cell differentiation; transcriptional regulation; in vivo infection models

Special Issue Information

Dear Colleagues,

Memory CD8 T cells that are retained after primary infection are important to establish improved protection upon secondary encounter with the pathogen. At least three subsets of memory cells have been defined that are referred to as central memory CD8 T cells (Tcm), effector memory CD8 T cells (Tem), and tissue-resident memory CD8 T cells (Trm). Tcm and Tem are circulating memory T cells that mediate body-wide immune surveillance in search of invading pathogens. In contrast, Trm permanently reside in peripheral barrier tissues, where they form a stationary defensive line of sentinels that alert the immune system upon pathogen re-encounter. Key to the potential of Trm to establish protective recall responses is their permanent location within the epithelia of the skin, lungs, and intestine at prime entry sites of pathogens. Substantial T_RM populations have also been observed in secondary lymphoid tissues and in internal organs, including brain, liver, and kidney, suggesting that Trm mediate immunosurveillance throughout tissues. More recently, it has become clear that memory T cells with similar characteristics as Trm are present in the tumor tissue of patients with melanoma, lung carcinoma, and ovarian carcinoma. The presence of these Trm-phenotype cells has been strongly associated with favorable outcomes for lung and ovarian carcinoma patients. Thus, Trm have emerged as one of the most powerful immune weapons in the barrier tissues to establish sterilizing immunity against re-encountered pathogens and to counter the outgrowth of solid tumors in the epithelia. However, once unleashed, Trm-driven immune responses may also have harmful side-effects on the integrity of the surrounding tissues. The emerging role of Trm as important instigators in driving inflammatory disease in skin (psoriasis and vitiligo), brain (multiple sclerosis), and intestine (ulcerative colitis and Crohn’s disease) underline the associated risks with the development of unwanted Trm responses against host tissues. These findings have positioned Trm at the frontline of research into vaccination strategies that elicit their differentiation in infectious disease or cancer and in therapies to prevent immunopathology in auto-immune disease. This Special Issue of Cells aims to improve our understanding of Trm by discussing their development, regulation, and function in both health and disease.

Dr. Jörg Hamann
Dr. Klaas van Gisbergen
Guest Editors

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Keywords

Memory T cells
Tissue protection
Viral infection
Tumor immunity
Autoimmunity

Published Papers (10 papers)

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Research

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16 pages, 4122 KiB

Open AccessFeature PaperArticle

The Inhibitory Receptor GPR56 (Adgrg1) Is Specifically Expressed by Tissue-Resident Memory T Cells in Mice But Dispensable for Their Differentiation and Function In Vivo

by Cheng-Chih Hsiao, Natasja A. M. Kragten, Xianhua Piao, Jörg Hamann and Klaas P. J. M. van Gisbergen

Cells 2021, 10(10), 2675; https://doi.org/10.3390/cells10102675 - 6 Oct 2021

Cited by 2 | Viewed by 2720

Abstract

Tissue-resident memory T (T_RM) cells with potent antiviral and antibacterial functions protect the epithelial and mucosal surfaces of our bodies against infection with pathogens. The strong proinflammatory activities of T_RM cells suggest requirement for expression of inhibitory molecules to restrain these memory T cells under steady state conditions. We previously identified the adhesion G protein-coupled receptor GPR56 as an inhibitory receptor of human cytotoxic lymphocytes that regulates their cytotoxic effector functions. Here, we explored the expression pattern, expression regulation, and function of GPR56 on pathogen-specific CD8⁺ T cells using two infection models. We observed that GPR56 is expressed on T_RM cells during acute infection and is upregulated by the T_RM cell-inducing cytokine TGF-β and the T_RM cell-associated transcription factor Hobit. However, GPR56 appeared dispensable for CD8⁺ T-cell differentiation and function upon acute infection with LCMV as well as Listeria monocytogenes. Thus, T_RM cells specifically acquire the inhibitory receptor GPR56, but the impact of this receptor on T_RM cells after acute infection does not appear essential to regulate effector functions of T_RM cells. Full article

(This article belongs to the Special Issue Tissue-Resident Memory T Cells)

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16 pages, 5647 KiB

Open AccessFeature PaperArticle

Single-Cell Transcriptomics Reveals Core Regulatory Programs That Determine the Heterogeneity of Circulating and Tissue-Resident Memory CD8⁺ T Cells

by Yao Chen, Jian Shen, Moujtaba Y. Kasmani, Paytsar Topchyan and Weiguo Cui

Cells 2021, 10(8), 2143; https://doi.org/10.3390/cells10082143 - 20 Aug 2021

Cited by 16 | Viewed by 5918

Abstract

During acute infections, CD8⁺ T cells form various memory subpopulations to provide long-lasting protection against reinfection. T central memory (TCM), T effector memory (TEM), and long-lived effector (LLE) cells are circulating memory populations with distinct plasticity, migration patterns, and effector functions. Tissue-resident memory (TRM) cells permanently reside in the frontline sites of pathogen entry and provide tissue-specific protection upon reinfection. Here, using single-cell RNA-sequencing (scRNA-seq) and bulk RNA-seq, we examined the different and shared transcriptomes and regulators of TRM cells with other circulating memory populations. Furthermore, we identified heterogeneity within the TRM pool from small intestine and novel transcriptional regulators that may control the phenotypic and functional heterogeneity of TRM cells during acute infection. Our findings provide a resource for future studies to identify novel pathways for enhancing vaccination and immunotherapeutic approaches. Full article

(This article belongs to the Special Issue Tissue-Resident Memory T Cells)

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18 pages, 3492 KiB

Open AccessArticle

CD8 and CD4 T Cell Populations in Human Kidneys

by Carlos van der Putten, Ester B.M. Remmerswaal, Matty L. Terpstra, Nelly D. van der Bom, Jesper Kers, Ineke J.M. ten Berge, Suzanne E. Geerlings, René A.W. van Lier, Frederike J. Bemelman and Michiel C. van Aalderen

Cells 2021, 10(2), 288; https://doi.org/10.3390/cells10020288 - 1 Feb 2021

Cited by 13 | Viewed by 2611

Abstract

Background: At border sites, and in internal organs, tissue resident memory T cells (T_RM) contribute to the immune barrier against pathogens like viruses, bacteria, fungi, and cancer. However, information on the presence and function of these cells in the human kidney is scant. In order to better understand the T cell-mediated immunological defense in this organ, we aimed to determine phenotypic and functional aspects of CD8 and CD4 T cells present in healthy and allograft kidney tissue. Methods: Using multichannel flow cytometry, we assessed the phenotype and function of T cells in healthy renal tissue samples (n = 5) and kidney allograft tissue (n = 7) and compared these aspects to T cells in peripheral blood from healthy controls (n = 13). Results: Kidney tissue samples contained substantial amounts of CD8 and CD4 T cells. In contrast to the circulating cells, kidney T cells frequently expressed CD69 and CD103, and were more often actively cycling. Furthermore, nearly all kidney T cells expressed CXCR3, and often expressed CXCR6 compared to T cells in the circulation. Markedly, kidney T cells produced greater quantities of IFNγ than circulating cells and were frequently polyfunctional. Conclusion: Functional T cells with the characteristic traits of T_RM reside in human kidney tissues. These cells are more often actively cycling and frequently express CXCR3 and CXCR6. Full article

(This article belongs to the Special Issue Tissue-Resident Memory T Cells)

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Review

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18 pages, 1195 KiB

Open AccessFeature PaperReview

Co-Ordination of Mucosal B Cell and CD8 T Cell Memory by Tissue-Resident CD4 Helper T Cells

by Young Min Son and Jie Sun

Cells 2021, 10(9), 2355; https://doi.org/10.3390/cells10092355 - 8 Sep 2021

Cited by 8 | Viewed by 6178

Abstract

Adaptive cellular immunity plays a major role in clearing microbial invasion of mucosal tissues in mammals. Following the clearance of primary pathogens, memory lymphocytes are established both systemically and locally at pathogen entry sites. Recently, resident memory CD8 T and B cells (T_RM and B_RM respectively), which are parked mainly in non-lymphoid mucosal tissues, were characterized and demonstrated to be essential for protection against secondary microbial invasion. Here we reviewed the current understanding of the cellular and molecular cues regulating CD8 T_RM and B_RM development, maintenance and function. We focused particularly on elucidating the role of a novel tissue-resident helper T (T_RH) cell population in assisting T_RM and B_RM responses in the respiratory mucosa following viral infection. Finally, we argue that the promotion of T_RH responses by future mucosal vaccines would be key to the development of successful universal influenza or coronavirus vaccines, providing long-lasting immunity against a broad spectrum of viral strains. Full article

(This article belongs to the Special Issue Tissue-Resident Memory T Cells)

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18 pages, 2522 KiB

Open AccessReview

The Potential of Tissue-Resident Memory T Cells for Adoptive Immunotherapy against Cancer

by Ammarina Beumer-Chuwonpad, Renske L. R. E. Taggenbrock, T. An Ngo and Klaas P. J. M. van Gisbergen

Cells 2021, 10(9), 2234; https://doi.org/10.3390/cells10092234 - 28 Aug 2021

Cited by 12 | Viewed by 5418

Abstract

Tissue-resident memory T cells (T_RM) comprise an important memory T cell subset that mediates local protection upon pathogen re-encounter. T_RM populations preferentially localize at entry sites of pathogens, including epithelia of the skin, lungs and intestine, but have also been observed in secondary lymphoid tissue, brain, liver and kidney. More recently, memory T cells characterized as T_RM have also been identified in tumors, including but not limited to melanoma, lung carcinoma, cervical carcinoma, gastric carcinoma and ovarian carcinoma. The presence of these memory T cells has been strongly associated with favorable clinical outcomes, which has generated an interest in targeting T_RM cells to improve immunotherapy of cancer patients. Nevertheless, intratumoral T_RM have also been found to express checkpoint inhibitory receptors, such as PD-1 and LAG-3. Triggering of such inhibitory receptors could induce dysfunction, often referred to as exhaustion, which may limit the effectiveness of T_RM in countering tumor growth. A better understanding of the differentiation and function of T_RM in tumor settings is crucial to deploy these memory T cells in future treatment options of cancer patients. The purpose of this review is to provide the current status of an important cancer immunotherapy known as TIL therapy, insight into the role of T_RM in the context of antitumor immunity, and the challenges and opportunities to exploit these cells for TIL therapy to ultimately improve cancer treatment. Full article

(This article belongs to the Special Issue Tissue-Resident Memory T Cells)

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12 pages, 1151 KiB

Open AccessReview

TGF-β: Many Paths to CD103⁺ CD8 T Cell Residency

by Zhijuan Qiu, Timothy H. Chu and Brian S. Sheridan

Cells 2021, 10(5), 989; https://doi.org/10.3390/cells10050989 - 23 Apr 2021

Cited by 23 | Viewed by 5280

Abstract

CD8 tissue-resident memory T (T_RM) cells primarily reside in nonlymphoid tissues without recirculating and provide front-line protective immunity against infections and cancers. CD8 T_RM cells can be generally divided into CD69⁺ CD103⁻ T_RM cells (referred to as CD103⁻ T_RM cells) and CD69⁺ CD103⁺ T_RM cells (referred to as CD103⁺ T_RM cells). TGF-β plays a critical role in the development and maintenance of CD103⁺ CD8 T_RM cells. In this review, we summarize the current understanding of tissue-specific activation of TGF-β mediated by integrins and how it contributes to CD103⁺ CD8 T_RM cell development and maintenance. Furthermore, we discuss the underlying mechanisms utilized by TGF-β to regulate the development and maintenance of CD103⁺ CD8 T_RM cells. Overall, this review highlights the importance of TGF-β in regulating this unique subset of memory CD8 T cells that may shed light on improving vaccine design to target this population. Full article

(This article belongs to the Special Issue Tissue-Resident Memory T Cells)

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18 pages, 1491 KiB

Open AccessReview

Tissue–Resident Memory T Cells in Chronic Inflammation—Local Cells with Systemic Effects?

by Anoushka Ashok Kumar Samat, Jolijn van der Geest, Sebastiaan J. Vastert, Jorg van Loosdregt and Femke van Wijk

Cells 2021, 10(2), 409; https://doi.org/10.3390/cells10020409 - 16 Feb 2021

Cited by 19 | Viewed by 5601

Abstract

Chronic inflammatory diseases such as rheumatoid arthritis (RA), Juvenile Idiopathic Arthritis (JIA), psoriasis, and inflammatory bowel disease (IBD) are characterized by systemic as well as local tissue inflammation, often with a relapsing-remitting course. Tissue–resident memory T cells (T_RM) enter non-lymphoid tissue (NLT) as part of the anamnestic immune response, especially in barrier tissues, and have been proposed to fuel chronic inflammation. T_RM display a distinct gene expression profile, including upregulation of CD69 and downregulation of CD62L, CCR7, and S1PR1. However, not all T_RM are consistent with this profile, and it is now more evident that the T_RM compartment comprises a heterogeneous population, with differences in their function and activation state. Interestingly, the paradigm of T_RM remaining resident in NLT has also been challenged. T cells with T_RM characteristics were identified in both lymph and circulation in murine and human studies, displaying similarities with circulating memory T cells. This suggests that re-activated T_RM are capable of retrograde migration from NLT via differential gene expression, mediating tissue egress and circulation. Circulating ‘ex-T_RM’ retain a propensity for return to NLT, especially to their tissue of origin. Additionally, memory T cells with T_RM characteristics have been identified in blood from patients with chronic inflammatory disease, leading to the hypothesis that T_RM egress from inflamed tissue as well. The presence of T_RM in both tissue and circulation has important implications for the development of novel therapies targeting chronic inflammation, and circulating ‘ex-T_RM’ may provide a vital diagnostic tool in the form of biomarkers. This review elaborates on the recent developments in the field of T_RM in the context of chronic inflammatory diseases. Full article

(This article belongs to the Special Issue Tissue-Resident Memory T Cells)

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17 pages, 1360 KiB

Open AccessReview

Functional Heterogeneity and Therapeutic Targeting of Tissue-Resident Memory T Cells

by Esmé T. I. van der Gracht, Felix M. Behr and Ramon Arens

Cells 2021, 10(1), 164; https://doi.org/10.3390/cells10010164 - 15 Jan 2021

Cited by 10 | Viewed by 3730

Abstract

Tissue-resident memory T (T_RM) cells mediate potent local innate and adaptive immune responses and provide long-lasting protective immunity. T_RM cells localize to many different tissues, including barrier tissues, and play a crucial role in protection against infectious and malignant disease. The formation and maintenance of T_RM cells are influenced by numerous factors, including inflammation, antigen triggering, and tissue-specific cues. Emerging evidence suggests that these signals also contribute to heterogeneity within the T_RM cell compartment. Here, we review the phenotypic and functional heterogeneity of CD8⁺ T_RM cells at different tissue sites and the molecular determinants defining CD8⁺ T_RM cell subsets. We further discuss the possibilities of targeting the unique cell surface molecules, cytokine and chemokine receptors, transcription factors, and metabolic features of T_RM cells for therapeutic purposes. Their crucial role in immune protection and their location at the frontlines of the immune defense make T_RM cells attractive therapeutic targets. A better understanding of the possibilities to selectively modulate T_RM cell populations may thus improve vaccination and immunotherapeutic strategies employing these potent immune cells. Full article

(This article belongs to the Special Issue Tissue-Resident Memory T Cells)

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13 pages, 12092 KiB

Open AccessReview

Human Tissue-Resident Memory T Cells in the Maternal–Fetal Interface. Lost Soldiers or Special Forces?

by Caitlin S. DeJong, Nicholas J. Maurice, Stephen A. McCartney and Martin Prlic

Cells 2020, 9(12), 2699; https://doi.org/10.3390/cells9122699 - 16 Dec 2020

Cited by 4 | Viewed by 3349

Abstract

The immune system plays a critical role during pregnancy, but the specific mechanisms and immune cell function needed to support pregnancy remain incompletely understood. Despite decades of research efforts, it is still unclear how the immune system maintains tolerance of fetal-derived tissues, which include most cells of the placenta and of course the fetus itself, without forfeiting the ability to protect against harmful infections. T cells recognize antigen in the context of major histocompatibility complex (MHC) encoded proteins, but classical MHC class I and II expression are diminished in fetal-derived cells. Can T cells present at the maternal–fetal interface (MFI) protect these cells from infection? Here we review what is known in regard to tissue-resident memory T (Trm) cells at the MFI. We mainly focus on how Trm cells can contribute to protection in the context of the unique features of the MFI, such as limited MHC expression as well as the temporary nature of the MFI, that are not found in other tissues. Full article

(This article belongs to the Special Issue Tissue-Resident Memory T Cells)

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22 pages, 3017 KiB

Open AccessReview

Tissue-Resident Memory T Cells in the Liver—Unique Characteristics of Local Specialists

by Lea M. Bartsch, Marcos P. S. Damasio, Sonu Subudhi and Hannah K. Drescher

Cells 2020, 9(11), 2457; https://doi.org/10.3390/cells9112457 - 11 Nov 2020

Cited by 17 | Viewed by 6262

Abstract

T cells play an important role to build up an effective immune response and are essential in the eradication of pathogens. To establish a long-lasting protection even after a re-challenge with the same pathogen, some T cells differentiate into memory T cells. Recently, a certain subpopulation of memory T cells at different tissue-sites of infection was detected—tissue-resident memory T cells (T_RM cells). These cells can patrol in the tissue in order to encounter their cognate antigen to establish an effective protection against secondary infection. The liver as an immunogenic organ is exposed to a variety of pathogens entering the liver through the systemic blood circulation or via the portal vein from the gut. It could be shown that intrahepatic T_RM cells can reside within the liver tissue for several years. Interestingly, hepatic T_RM cell differentiation requires a distinct cytokine milieu. In addition, T_RM cells express specific surface markers and transcription factors, which allow their identification delimited from their circulating counterparts. It could be demonstrated that liver T_RM cells play a particular role in many liver diseases such as hepatitis B and C infection, non-alcoholic fatty liver disease and even play a role in the development of hepatocellular carcinoma and in building long-lasting immune responses after vaccination. A better understanding of intrahepatic T_RM cells is critical to understand the pathophysiology of many liver diseases and to identify new potential drug targets for the development of novel treatment strategies. Full article

(This article belongs to the Special Issue Tissue-Resident Memory T Cells)

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