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Barros, Leandro, Cristina Ferreira, and Marc Veldhoen. "The fellowship of regulatory and tissue-resident memory cells." Mucosal Immunology 15, no. 1 (October 4, 2021): 64–73. http://dx.doi.org/10.1038/s41385-021-00456-w.
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AbstractT cells located in non-lymphoid tissues have come to prominence in recent years. CD8+ tissue-resident memory (Trm) cells are important for tissue immune surveillance, provide an important line of defence against invading pathogens and show promise in cancer therapies. These cells differ in phenotype from other memory populations, are adapted to the tissue they home to where they found their cognate antigen and have different metabolic requirements for survival and activation. CD4+ Foxp3+ regulatory T (Treg) cells also consist of specialised populations, found in non-lymphoid tissues, with distinct transcriptional programmes. These cells have equally adapted to function in the tissue they made their home. Both Trm and Treg cells have functions beyond immune defence, involving tissue homeostasis, repair and turnover. They are part of a multicellular communication network. Intriguingly, occupying the same niche, Treg cells are important in the establishment of Trm cells, which may have implications to harness the immune surveillance and tissue homeostasis properties of Trm cells for future therapies.
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DiSpirito, Joanna R., David Zemmour, Deepshika Ramanan, Jun Cho, Rapolas Zilionis, Allon M. Klein, Christophe Benoist, and Diane Mathis. "Molecular diversification of regulatory T cells in nonlymphoid tissues." Science Immunology 3, no. 27 (September 14, 2018): eaat5861. http://dx.doi.org/10.1126/sciimmunol.aat5861.
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Foxp3+CD4+regulatory T cells (Tregs) accumulate in certain nonlymphoid tissues, where they control diverse aspects of organ homeostasis. Populations of tissue Tregs, as they have been termed, have transcriptomes distinct from those of their counterparts in lymphoid organs and other nonlymphoid tissues. We examined the diversification of Tregsin visceral adipose tissue, skeletal muscle, and the colon vis-à-vis lymphoid organs from the same individuals. The unique transcriptomes of the various tissue Tregpopulations resulted from layering of tissue-restricted open chromatin regions over regions already open in the spleen, the latter tagged by super-enhancers and particular histone marks. The binding motifs for a small number of transcription factor (TF) families were repeatedly enriched within the accessible chromatin stretches of Tregsin the three nonlymphoid tissues. However, a bioinformatically and experimentally validated transcriptional network, constructed by integrating chromatin accessibility and single-cell transcriptomic data, predicted reliance on different TF families in the different tissues. The network analysis also revealed that tissue-restricted and broadly acting TFs were integrated into feed-forward loops to enforce tissue-specific gene expression in nonlymphoid-tissue Tregs. Overall, this study provides a framework for understanding the epigenetic dynamics of T cells operating in nonlymphoid tissues, which should inform strategies for specifically targeting them.
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Ley, Klaus. "The second touch hypothesis: T cell activation, homing and polarization." F1000Research 3 (February 5, 2014): 37. http://dx.doi.org/10.12688/f1000research.3-37.v1.
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The second touch hypothesis states that T cell activation, proliferation, induction of homing receptors and polarization are distinguishable and, at least in part, sequential. The second touch hypothesis maintains that full T cell polarization requires T cell interaction with antigen-presenting cells (DCs, macrophages, B cells and certain activated stromal cells) in the non-lymphoid tissue where the antigen resides. Upon initial antigen encounter in peripheral lymph nodes (PLN), T cells become activated, proliferate and express homing receptors that enable them to recirculate to the (inflamed) tissue that contains the antigen. Differentiation into the T helper lineages Th1, Th2, Th17 and induced regulatory T cells (iTreg) requires additional antigen presentation by tissue macrophages and other antigen presenting cells (APCs) in the inflamed tissue. Here, I present a conceptual framework for the importance of peripheral (non-lymphoid) antigen presentation to antigen-experienced T cells.
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Ley, Klaus. "The second touch hypothesis: T cell activation, homing and polarization." F1000Research 3 (August 4, 2014): 37. http://dx.doi.org/10.12688/f1000research.3-37.v2.
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The second touch hypothesis states that T cell activation, proliferation, induction of homing receptors and polarization are distinguishable and, at least in part, sequential. The second touch hypothesis maintains that full T cell polarization requires T cell interaction with antigen-presenting cells (DCs, macrophages, B cells and certain activated stromal cells) in the non-lymphoid tissue where the antigen resides. Upon initial antigen encounter in peripheral lymph nodes (PLN), T cells become activated, proliferate and express homing receptors that enable them to recirculate to the (inflamed) tissue that contains the antigen. Differentiation into the T helper lineages Th1, Th2, Th17 and induced regulatory T cells (iTreg) requires additional antigen presentation by tissue macrophages and other antigen presenting cells (APCs) in the inflamed tissue. Here, I present a conceptual framework for the importance of peripheral (non-lymphoid) antigen presentation to antigen-experienced T cells.
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Gu, Yisu, Emily Thornton, and Fiona Powrie. "Spatial Compartmentalisation of T Regulatory Cells within Intestinal Lymphoid Tissue." Biology of Blood and Marrow Transplantation 25, no. 3 (March 2019): S297. http://dx.doi.org/10.1016/j.bbmt.2018.12.676.
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Daynes, R. A., B. A. Araneo, T. A. Dowell, K. Huang, and D. Dudley. "Regulation of murine lymphokine production in vivo. III. The lymphoid tissue microenvironment exerts regulatory influences over T helper cell function." Journal of Experimental Medicine 171, no. 4 (April 1, 1990): 979–96. http://dx.doi.org/10.1084/jem.171.4.979.
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We investigated the capacity of murine T lymphocytes, isolated from various lymphoid organs of normal or antigen-primed donors, to produce IL-2 or IL-4 after activation with anti-CD3 or specific antigen. Our results established that T cells resident within lymphoid organs being drained by nonmucosal tissue sites (e.g., axillary, inguinal, brachial lymph nodes, or spleen) produced IL-2 as the predominant T cell growth factor (TCGF) after activation. Conversely, activated T cells from lymphoid organs being drained by mucosal tissues (Peyer's patches, and cervical, periaortic, and parathymic lymph nodes) produced IL-4 as the major species of TCGF. Analysis of the lymphoid tissues obtained from adoptive recipients of antigen-primed lymphocytes provided by syngeneic donors provided evidence that direct influences were being exerted on T cells during their residence within defined lymphoid compartments. These lymphoid tissue influences appeared to be responsible for altering the potential of resident T cells to produce distinct species of TCGF. Steroid hormones, known transcriptional enhancers and repressors of specific cellular genes, were implicated in the controlling mechanisms over TCGF production. Glucocorticoids (GCs) were found to exert a systemic effect on all recirculating T cells, evidenced by a marked dominance in IL-4 production by T cells obtained from all lymphoid organs of GC-treated mice, or after a direct exposure of normal lymphoid cells to GCs in vitro before cellular activation with T cell mitogens. Further, the androgen steroid DHEA appeared to be responsible for providing an epigenetic influence to T cells trafficking through peripheral lymphoid organs. This steroid influence resulted in an enhanced potential for IL-2 secretion after activation. Anatomic compartmentalization of the DHEA-facilitated influence appears to be mediated by differential levels of DHEA-sulfatase in lymphoid tissues. DHEA-sulfatase is an enzyme capable of converting DHEA-sulfate (inactive) to the active hormone DHEA. We find very high activities of this enzyme isolated in murine macrophages. The implications of our findings to immunobiology are very great, and indicate that T cells, while clonally restricted for antigen peptide recognition, also appear to exhibit an extreme flexibility with regards to the species of lymphokines they produce after activation. Regulation of this highly conservative mechanism appears to be partially, if not exclusively, controlled by cellular influences being exerted by distinct species of steroid hormones, supplied in an endocrine or a paracrine manner where they mediate either systemic or tissue-localized influences, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)
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Peters, Jorieke H., Hans J. P. M. Koenen, Esther Fasse, Henk J. Tijssen, Jan N. M. IJzermans, Patricia J. T. A. Groenen, Nicolaas P. M. Schaap, Jaap Kwekkeboom, and Irma Joosten. "Human secondary lymphoid organs typically contain polyclonally-activated proliferating regulatory T cells." Blood 122, no. 13 (September 26, 2013): 2213–23. http://dx.doi.org/10.1182/blood-2013-03-489443.
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Key Points The majority of suppressive Tregs in human secondary lymphoid organs are activated, produce cytokines, and proliferate. Human lymphoid organs may provide a platform for in vivo expansion of infused Tregs and subsequent tissue-directed homing.
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Hewavisenti, Rehana V., Angela L. Ferguson, Georgia Gasparini, Tomoki Ohashi, Asolina Braun, Thomas S. Watkins, John J. Miles, et al. "Tissue‐resident regulatory T cells accumulate at human barrier lymphoid organs." Immunology & Cell Biology 99, no. 8 (July 27, 2021): 894–906. http://dx.doi.org/10.1111/imcb.12481.
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Kocks, Jessica R., Ana Clara Marques Davalos-Misslitz, Gabriele Hintzen, Lars Ohl, and Reinhold Förster. "Regulatory T cells interfere with the development of bronchus-associated lymphoid tissue." Journal of Experimental Medicine 204, no. 4 (March 19, 2007): 723–34. http://dx.doi.org/10.1084/jem.20061424.
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Presence and extent of bronchus-associated lymphoid tissue (BALT) is subject to considerable variations between species and is only occasionally observed in lungs of mice. Here we demonstrate that mice deficient for the chemokine receptor CCR7 regularly develop highly organized BALT. These structures were not present at birth but were detectable from day 5 onwards. Analyzing CCR7−/−/wild-type bone marrow chimeras, we demonstrate that the development of BALT is caused by alterations of the hematopoietic system in CCR7-deficient mice. These observations together with the finding that CCR7-deficient mice posses dramatically reduced numbers of regulatory T cells (T reg cells) in the lung-draining bronchial lymph node suggest that BALT formation might be caused by disabled in situ function of T reg cells. Indeed, although adoptive transfer of wild-type T reg cells to CCR7-deficient recipients resulted in a profound reduction of BALT formation, neither naive wild-type T cells nor T reg cells from CCR7−/− donors impair BALT generation. Furthermore, we provide evidence that CCR7-deficient T reg cells, although strongly impaired in homing to peripheral lymph nodes, are fully effective in vitro. Thus our data reveal a CCR7-dependent homing of T reg cells to peripheral lymph nodes in conjunction with a role for these cells in controlling BALT formation.
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Graca, Luis, Stephen P. Cobbold, and Herman Waldmann. "Identification of Regulatory T Cells in Tolerated Allografts." Journal of Experimental Medicine 195, no. 12 (June 10, 2002): 1641–46. http://dx.doi.org/10.1084/jem.20012097.
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Induction of transplantation tolerance with certain therapeutic nondepleting monoclonal antibodies can lead to a robust state of peripheral “dominant” tolerance. Regulatory CD4+ T cells, which mediate this form of “dominant” tolerance, can be isolated from spleens of tolerant animals. To determine whether there were any extra-lymphoid sites that might harbor regulatory T cells we sought their presence in tolerated skin allografts and in normal skin. When tolerated skin grafts are retransplanted onto T cell–depleted hosts, graft-infiltrating T cells exit the graft and recolonize the new host. These colonizing T cells can be shown to contain members with regulatory function, as they can prevent nontolerant lymphocytes from rejecting fresh skin allografts, without hindrance of rejection of third party skin. Our results suggest that T cell suppression of graft rejection is an active process that operates beyond secondary lymphoid tissue, and involves the persistent presence of regulatory T cells at the site of the tolerated transplant.
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Amouzegar, Afsaneh, and Sunil K. Chauhan. "Effector and Regulatory T Cell Trafficking in Corneal Allograft Rejection." Mediators of Inflammation 2017 (2017): 1–6. http://dx.doi.org/10.1155/2017/8670280.
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Corneal transplantation is among the most prevalent and successful forms of solid tissue transplantation in humans. Failure of corneal allograft is mainly due to immune-mediated destruction of the graft, a complex and highly coordinated process that involves elaborate interactions between cells of innate and adaptive immunity. The migration of immune cells to regional lymphoid tissues and to the site of graft plays a central role in the immunopathogenesis of graft rejection. Intricate interactions between adhesion molecules and their counter receptors on immune cells in conjunction with tissue-specific chemokines guide the trafficking of these cells to the draining lymph nodes and ultimately to the site of graft. In this review, we discuss the cascade of chemokines and adhesion molecules that mediate the trafficking of effector and regulatory T cells during corneal allograft rejection.
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Yu, Hua, Nicola Gagliani, Harumichi Ishigame, Samuel Huber, Shu Zhu, Enric Esplugues, Kevan C. Herold, Li Wen, and Richard A. Flavell. "Intestinal type 1 regulatory T cells migrate to periphery to suppress diabetogenic T cells and prevent diabetes development." Proceedings of the National Academy of Sciences 114, no. 39 (September 11, 2017): 10443–48. http://dx.doi.org/10.1073/pnas.1705599114.
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Growing insight into the pathogenesis of autoimmune diseases and numerous studies in preclinical models highlights the potential of regulatory T cells to restore tolerance. By using non-obese diabetic (NOD) BDC2.5 TCR-transgenic (Tg), and IL-10 and Foxp3 double-reporter mice, we demonstrate that alteration of gut microbiota during cohousing experiments or treatment with anti-CD3 mAb significantly increase intestinal IL-10–producing type 1 regulatory T (Tr1) cells and decrease diabetes incidence. These intestinal antigen-specific Tr1 cells have the ability to migrate to the periphery via a variety of chemokine receptors such as CCR4, CCR5, and CCR7 and to suppress proliferation of Th1 cells in the pancreas. The ability of Tr1 cells to cure diabetes in NOD mice required IL-10 signaling, as Tr1 cells could not suppress CD4+ T cells with a dominant-negative IL-10R. Taken together, our data show a key role of intestinal Tr1 cells in the control of effector T cells and development of diabetes. Therefore, modulating gut-associated lymphoid tissue to boost Tr1 cells may be important in type 1 diabetes management.
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Messing, Melina, Sia Cecilia Jan-Abu, and Kelly McNagny. "Group 2 Innate Lymphoid Cells: Central Players in a Recurring Theme of Repair and Regeneration." International Journal of Molecular Sciences 21, no. 4 (February 17, 2020): 1350. http://dx.doi.org/10.3390/ijms21041350.
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Innate lymphoid cells (ILCs) are recently discovered innate counterparts to the well-established T helper cell subsets and are most abundant at barrier surfaces, where they participate in tissue homeostasis and inflammatory responses against invading pathogens. Group 2 innate lymphoid cells (ILC2s) share cytokine and transcription factor expression profiles with type-2 helper T cells and are primarily associated with immune responses against allergens and helminth infections. Emerging data, however, suggests that ILC2s are also key regulators in other inflammatory settings; both in a beneficial context, such as the establishment of neonatal immunity, tissue repair, and homeostasis, and in the context of pathological tissue damage and disease, such as fibrosis development. This review focuses on the interactions of ILC2s with stromal cells, eosinophils, macrophages, and T regulatory cells that are common to the different settings in which type-2 immunity has been explored. We further discuss how an understanding of these interactions can reveal new avenues of therapeutic tissue regeneration, where the role of ILC2s is yet to be fully established.
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Chung, Douglas C., Nicolas Jacquelot, Maryam Ghaedi, Kathrin Warner, and Pamela S. Ohashi. "Innate Lymphoid Cells: Role in Immune Regulation and Cancer." Cancers 14, no. 9 (April 21, 2022): 2071. http://dx.doi.org/10.3390/cancers14092071.
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Immune regulation is composed of a complex network of cellular and molecular pathways that regulate the immune system and prevent tissue damage. It is increasingly clear that innate lymphoid cells (ILCs) are also armed with immunosuppressive capacities similar to well-known immune regulatory cells (i.e., regulatory T cells). In cancer, immunoregulatory ILCs have been shown to inhibit anti-tumour immune response through various mechanisms including: (a) direct suppression of anti-tumour T cells or NK cells, (b) inhibiting T-cell priming, and (c) promoting other immunoregulatory cells. To provide a framework of understanding the role of immunosuppressive ILCs in the context of cancer, we first outline a brief history and challenges related to defining immunosuppressive ILCs. Furthermore, we focus on the mechanisms of ILCs in suppressing anti-tumour immunity and consequentially promoting tumour progression.
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Zhao, Hai-Mei, Rong Xu, Xiao-Ying Huang, Shao-Min Cheng, Min-Fang Huang, Hai-Yang Yue, Xin Wang, Yong Zou, Ai-Ping Lu, and Duan-Yong Liu. "Curcumin improves regulatory T cells in gut-associated lymphoid tissue of colitis mice." World Journal of Gastroenterology 22, no. 23 (2016): 5374. http://dx.doi.org/10.3748/wjg.v22.i23.5374.
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Sun, Cheng-Ming, Jason A. Hall, Rebecca B. Blank, Nicolas Bouladoux, Mohamed Oukka, J. Rodrigo Mora, and Yasmine Belkaid. "Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid." Journal of Experimental Medicine 204, no. 8 (July 9, 2007): 1775–85. http://dx.doi.org/10.1084/jem.20070602.
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To maintain immune homeostasis, the intestinal immune system has evolved redundant regulatory strategies. In this regard, the gut is home to a large number of regulatory T (T reg) cells, including the Foxp3+ T reg cell. Therefore, we hypothesized that the gut environment preferentially supports extrathymic T reg cell development. We show that peripheral conversion of CD4+ T cells to T reg cells occurs primarily in gut-associated lymphoid tissue (GALT) after oral exposure to antigen and in a lymphopenic environment. Dendritic cells (DCs) purified from the lamina propria (Lp; LpDCs) of the small intestine were found to promote a high level of T reg cell conversion relative to lymphoid organ–derived DCs. This enhanced conversion by LpDCs was dependent on TGF-β and retinoic acid (RA), which is a vitamin A metabolite highly expressed in GALT. Together, these data demonstrate that the intestinal immune system has evolved a self-contained strategy to promote T reg cell neoconversion.
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Wirsching, Sebastian, Michael Fichter, Maximiliano L. Cacicedo, Katharina Landfester, and Stephan Gehring. "Modification of Regulatory T Cell Epitopes Promotes Effector T Cell Responses to Aspartyl/Asparaginyl β-Hydroxylase." International Journal of Molecular Sciences 23, no. 20 (October 18, 2022): 12444. http://dx.doi.org/10.3390/ijms232012444.
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Cancer is a leading cause of death worldwide. The search for innovative therapeutic approaches is a principal focus of medical research. Vaccine strategies targeting a number of tumor-associated antigens are currently being evaluated. To date, none have garnered significant success. Purportedly, an immunosuppressive tumor microenvironment and the accumulation of regulatory T cells contribute to a lack of tumor vaccine efficacy. Aspartyl/asparaginyl β-hydroxylase (ASPH), a promising therapeutic target, is overexpressed in a variety of malignant tumors but is expressed negligibly in normal tissues. Computer analysis predicted that ASPH expresses four peptide sequences (epitopes) capable of stimulating regulatory T cell activity. The abolition of these putative regulatory T cell epitopes increased the CD4+ and CD8+ effector T cell responses to monocyte-derived dendritic cells pulsed with a modified, epitope-depleted version of ASPH in an ex vivo human lymphoid tissue-equivalent coculture system while simultaneously decreasing the overall number of FoxP3+ regulatory T cells. These findings suggest that the efficacy of all new vaccine candidates would profit from screening and eliminating potential tolerogenic regulatory T cell epitopes.
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Chauhan, Sunil K., Daniel R. Saban, Thomas H. Dohlman, and Reza Dana. "CCL-21 Conditioned Regulatory T Cells Induce Allotolerance through Enhanced Homing to Lymphoid Tissue." Journal of Immunology 192, no. 2 (December 11, 2013): 817–23. http://dx.doi.org/10.4049/jimmunol.1203469.
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Hue, Susan Swee-Shan, Siok-Bian Ng, Shi Wang, and Soo-Yong Tan. "Cellular Origins and Pathogenesis of Gastrointestinal NK- and T-Cell Lymphoproliferative Disorders." Cancers 14, no. 10 (May 18, 2022): 2483. http://dx.doi.org/10.3390/cancers14102483.
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The intestinal immune system, which must ensure appropriate immune responses to both pathogens and commensal microflora, comprises innate lymphoid cells and various T-cell subsets, including intra-epithelial lymphocytes (IELs). An example of innate lymphoid cells is natural killer cells, which may be classified into tissue-resident, CD56bright NK-cells that serve a regulatory function and more mature, circulating CD56dim NK-cells with effector cytolytic properties. CD56bright NK-cells in the gastrointestinal tract give rise to indolent NK-cell enteropathy and lymphomatoid gastropathy, as well as the aggressive extranodal NK/T cell lymphoma, the latter following activation by EBV infection and neoplastic transformation. Conventional CD4+ TCRαβ+ and CD8αβ+ TCRαβ+ T-cells are located in the lamina propria and the intraepithelial compartment of intestinal mucosa as type ‘a’ IELs. They are the putative cells of origin for CD4+ and CD8+ indolent T-cell lymphoproliferative disorders of the gastrointestinal tract and intestinal T-cell lymphoma, NOS. In addition to such conventional T-cells, there are non-conventional T-cells in the intra-epithelial compartment that express CD8αα and innate lymphoid cells that lack TCRs. The central feature of type ‘b’ IELs is the expression of CD8αα homodimers, seen in monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), which primarily arises from both CD8αα+ TCRαβ+ and CD8αα+ TCRγδ+ IELs. EATL is the other epitheliotropic T-cell lymphoma in the GI tract, a subset of which arises from the expansion and reprograming of intracytoplasmic CD3+ innate lymphoid cells, driven by IL15 and mutations of the JAK-STAT pathway.
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Seehus, Corey R., and Jonathan Kaye. "The Role of TOX in the Development of Innate Lymphoid Cells." Mediators of Inflammation 2015 (2015): 1–7. http://dx.doi.org/10.1155/2015/243868.
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TOX, an evolutionarily conserved member of the HMG-box family of proteins, is essential for the development of various cells of both the innate and adaptive immune system. TOX is required for the development of CD4+T lineage cells in the thymus, including natural killer T and T regulatory cells, as well as development of natural killer cells and fetal lymphoid tissue inducer cells, the latter required for lymph node organogenesis. Recently, we have identified a broader role for TOX in the innate immune system, demonstrating that this nuclear protein is required for generation of bone marrow progenitors that have potential to give rise to all innate lymphoid cells. Innate lymphoid cells, classified according to transcription factor expression and cytokine secretion profiles, derive from common lymphoid progenitors in the bone marrow and require Notch signals for their development. We discuss here the role of TOX in specifying CLP toward an innate lymphoid cell fate and hypothesize a possible role for TOX in regulating Notch gene targets during innate lymphoid cell development.
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Riegel, Christin, Tina J. Boeld, Kristina Doser, Elisabeth Huber, Petra Hoffmann, and Matthias Edinger. "Efficient treatment of murine acute GvHD by in vitro expanded donor regulatory T cells." Leukemia 34, no. 3 (November 12, 2019): 895–908. http://dx.doi.org/10.1038/s41375-019-0625-3.
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Abstract Acute graft-versus-host disease (aGvHD) is a frequent complication after allogeneic bone marrow/stem cell transplantation (BMT/SCT) induced by co-transplanted alloreactive conventional donor T cells. We previously demonstrated that the adoptive transfer of donor CD4+CD25+Foxp3+ regulatory T cells (Treg) at the time of BMT prevents aGvHD in murine models. Yet, the therapeutic potential of donor Treg for the treatment of established aGvHD has not yet been studied in detail. We now used in vitro expanded phenotypically and functionally stable murine Treg to explore their therapeutic efficacy in haploidentical aGvHD models. Upon transfer donor Treg ameliorate clinical and histologic signs of aGvHD and significantly improve survival. They migrate to lymphoid as well as aGvHD target organs, predominantly the gastrointestinal tract, where they inhibit the proliferation of conventional T cells, reduce the influx of myeloid cells, and the accumulation of inflammatory cytokines. Successfully treated animals restore aGvHD-induced tissue damage in target organs and lymphoid tissues, thereby supporting lymphocyte reconstitution. The therapeutically applied Treg population survives long term without conversion into pathogenic effector T cells. These results demonstrate that donor Treg not only prevent aGvHD, but are also efficacious for the treatment of this life-threatening BMT complication.
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Wu, Douglas C., Joanna Wieckiewicz, and Kathryn J. Wood. "HUMAN REGULATORY T CELLS PREVENT ISLET ALLOGRAFT REJECTION." Clinical & Investigative Medicine 31, no. 4 (August 1, 2008): 25. http://dx.doi.org/10.25011/cim.v31i4.4832.
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Background: Type 1 diabetes mellitus represents a significant burden on global healthcare. Pancreatic islet transplantation offers an effective means of controlling the disease, but shortage of donor tissue, graft thrombosis, and immunological rejection after transplantation remain obstacles that need to be overcome. Our aim was to assess the ability of ex vivo expanded human regulatory T cells (Treg) in modulating the rejection response against a human islet allograft in a clinically relevant model of human pancreatic islet transplantation. Methods: We studied the rejection response against allogeneic human islets in acohort of 32 immunodeficient mice which had been reconstituted with a functional human immune system. Thirteen subjects were transplanted with human islets without further immunological modification; graft survival was compared with that of thirteen subjects treated additionally with human regulatory T cells. Six controls were given a human islet transplant, but not reconstituted with human immune cells to demonstrate the functionality of the islet graft in the absence of immunological rejection. Graft function was assessed with serial blood glucose measurements, immunohistochemistry,immunoflourescence, and flow cytometry. Findings: Human islet allografts were rapidly rejected in subjects that did notreceive Treg. With Treg treatment, however, human islet allograft rejection was prevented (median survival time (MST) of > 45 days with Treg, as opposed to an MST of 23 days without Treg). Ex vivo expanded Treg homed to the lymphoid tissue draining the graft site where they suppressed the priming, activation, proliferation, and effector cytokine production of alloreactive T cells. Interpretation: These findings in a clinically relevant model of human pancreatic islet transplantation demonstrate the ability of ex vivo expanded human Treg to attenuate acute islet allograft rejection, and provide further support for their use in cellular immunotherapy.
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Stanisavljević, S., J. Lukić, M. Momčilović, M. Miljković, B. Jevtić, M. Kojić, N. Golić, M. Mostarica Stojković, and D. Miljković. "Gut-associated lymphoid tissue, gut microbes and susceptibility to experimental autoimmune encephalomyelitis." Beneficial Microbes 7, no. 3 (June 1, 2016): 363–73. http://dx.doi.org/10.3920/bm2015.0159.
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Gut microbiota and gut-associated lymphoid tissue have been increasingly appreciated as important players in pathogenesis of various autoimmune diseases, including multiple sclerosis. Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis that can be induced with an injection of spinal cord homogenate emulsified in complete Freund’s adjuvant in Dark Agouti (DA) rats, but not in Albino Oxford (AO) rats. In this study, mesenteric lymph nodes (MLN), Peyer’s patches (PP) and gut microbiota were analysed in these two rat strains. There was higher proportion of CD4+ T cells and regulatory T cells in non-immunised DA rats in comparison to AO rats. Also, DA rat MLN and PP cells were higher producers of pro-inflammatory cytokines interferon-γ and interleukin-17. Finally, microbial analyses showed that uncultivated species of Turicibacter and Atopostipes genus were exclusively present in AO rats, in faeces and intestinal tissue, respectively. Thus, it is clear that in comparison of an EAE-susceptible with an EAE-resistant strain of rats, various discrepancies at the level of gut associated lymphoid tissue, as well as at the level of gut microbiota can be observed. Future studies should determine if the differences have functional significance for EAE pathogenesis.
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Wasnik, Samiksha, David J. Baylink, Jianmei Leavenworth, Chenfan Liu, Hongzheng Bi, and Xiaolei Tang. "Towards Clinical Translation of CD8+ Regulatory T Cells Restricted by Non-Classical Major Histocompatibility Complex Ib Molecules." International Journal of Molecular Sciences 20, no. 19 (September 28, 2019): 4829. http://dx.doi.org/10.3390/ijms20194829.
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In central lymphoid tissues, mature lymphocytes are generated and pathogenic autoreactive lymphocytes are deleted. However, it is currently known that a significant number of potentially pathogenic autoreactive lymphocytes escape the deletion and populate peripheral lymphoid tissues. Therefore, peripheral mechanisms are present to prevent these potentially pathogenic autoreactive lymphocytes from harming one’s own tissues. One such mechanism is dictated by regulatory T (Treg) cells. So far, the most extensively studied Treg cells are CD4+Foxp3+ Treg cells. However, recent clinical trials for the treatment of immune-mediated diseases using CD4+ Foxp3+ Treg cells met with limited success. Accordingly, it is necessary to explore the potential importance of other Treg cells such as CD8+ Treg cells. In this regard, one extensively studied CD8+ Treg cell subset is Qa-1(HLA-E in human)-restricted CD8+ Treg cells, in which Qa-1(HLA-E) molecules belong to a group of non-classical major histocompatibility complex Ib molecules. This review will first summarize the evidence for the presence of Qa-1-restricted CD8+ Treg cells and their regulatory mechanisms. Major discussions will then focus on the potential clinical translation of Qa-1-restricted CD8+ Treg cells. At the end, we will briefly discuss the current status of human studies on HLA-E-restricted CD8+ Treg cells as well as potential future directions.
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Gulubova, M., M. Hadzhi, L. Hadzhiilieva, D. Chonov, and M. M. Ignatova. "Dendritic Cells and T Cell Subsets in the Development of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis." Acta Medica Bulgarica 48, no. 3 (October 1, 2021): 49–55. http://dx.doi.org/10.2478/amb-2021-0037.
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Abstract Nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are associated with steatosis, inflammation and fibrosis. Liver dendritic cells (DCs) are usually tolerogenic in the sinusoidal milleu composed of immunosuppressive cytokines. In NAFLD and NASH, DCs become pro-inflammatory and modulate hepatic immune response. Murine liver DCs are three major subtypes: classical (lymphoid) cDC1 or the crosspresenters (CD8α+CD103+), classical (myeloid) cDC2 (CD11b+) and plasmacytoid pDCs (PDCA-1+Siglec-H+) and two additional subtypes or lymphoid + myeloid DCs and NKDCs. Similarly, human liver DCs are three subtypes or CD141+CLEC9A+, CD1c+ (BDCA1+) and pDCs (CD303+BDCA2+). Compared to blood human hepatic DCs are less immature and predominantly induce regulatory T cells (Tregs) and IL-4 secreting T cells (Th2). DCs polarize T cells into different Th types that are in interrelations in NAFLD/NASH. T helper 1 (Th1) (T-bet) cells are associated with adipose tissue inflammation. The differentiation of Th2 (GATA3) cells is induced by IL-4 DCs, increased in NAFLD. Similarly, Th17 cells (RORγt/ RORc) are increased in NAFLD and NASH. Tregs (FoxP3) are increased in the liver in steatosis and Th22 cells (AHR) are elevated in diabetes mellitus 2 (DM2) and adiposity. CD8+ T cells γδT cells and MAIT cells also contribute to liver inflammation.
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Smigiel, Kate S., Elizabeth Richards, Shivani Srivastava, Kerri R. Thomas, Jan C. Dudda, Kimberly D. Klonowski, and Daniel J. Campbell. "CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets." Journal of Experimental Medicine 211, no. 1 (December 30, 2013): 121–36. http://dx.doi.org/10.1084/jem.20131142.
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Immune tolerance and activation depend on precise control over the number and function of immunosuppressive Foxp3+ regulatory T (T reg) cells, and the importance of IL-2 in maintaining tolerance and preventing autoimmunity is clear. However, the homeostatic requirement for IL-2 among specific populations of peripheral T reg cells remains poorly understood. We show that IL-2 selectively maintains a population of quiescent CD44loCD62Lhi T reg cells that gain access to paracrine IL-2 produced in the T cell zones of secondary lymphoid tissues due to their expression of the chemokine receptor CCR7. In contrast, CD44hiCD62LloCCR7lo T reg cells that populate nonlymphoid tissues do not access IL-2–prevalent regions in vivo and are insensitive to IL-2 blockade; instead, their maintenance depends on continued signaling through the co-stimulatory receptor ICOS (inducible co-stimulator). Thus, we define a fundamental homeostatic subdivision in T reg cell populations based on their localization and provide an integrated framework for understanding how T reg cell abundance and function are controlled by unique signals in different tissue environments.
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Nguyen, Vu H., Robert Zeiser, Daniel L. daSilva, Daisy S. Chang, Andreas Beilhack, Christopher H. Contag, and Robert S. Negrin. "In vivo dynamics of regulatory T-cell trafficking and survival predict effective strategies to control graft-versus-host disease following allogeneic transplantation." Blood 109, no. 6 (November 9, 2006): 2649–56. http://dx.doi.org/10.1182/blood-2006-08-044529.
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Abstract CD4+CD25+ regulatory T cells (Tregs) suppress immune responses to alloantigens. The in vivo circulation and tissue localization of Tregs during an adaptive immune response remain unclear. We noninvasively tracked luciferase-expressing Tregs over time in an allogeneic bone marrow transplant model and demonstrated colocalization with effector T cells and initial expansion in secondary lymphoid organs before migration into inflamed tissues. Inflammation induced by irradiation and the allogeneic setting provided crucial stimuli for early Treg expansion and migration, leading to parallel reduction of effector T-cell proliferation in lymphoid organs and peripheral tissues. Treg transplants conferred long-term protection from systemic inflammatory challenge consistent with Treg in vivo survival. Suppression occurred during multiple phases of inflammation, but is optimal in the initial phase, providing protection from graft-versus-host disease while maintaining the graft-versus-tumor effect even at physiologic doses of Tregs due to their in vivo expansion, hence overcoming a major barrier to potential clinical applications of Tregs given their rarity.
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Nakahara, Takeshi, Hiroshi Uchi, Alexander M. Lesokhin, Francesca Avogadri, Gabrielle A. Rizzuto, Daniel Hirschhorn-Cymerman, Katherine S. Panageas, Taha Merghoub, Jedd D. Wolchok, and Alan N. Houghton. "Cyclophosphamide enhances immunity by modulating the balance of dendritic cell subsets in lymphoid organs." Blood 115, no. 22 (June 3, 2010): 4384–92. http://dx.doi.org/10.1182/blood-2009-11-251231.
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Abstract Cyclophosphamide (CTX), a commonly used chemotherapeutic agent can enhance immune responses. The ability of CTX to promote the proliferation of effector T cells and abrogate the function of regulatory T cells (Tregs) has been described. In this study, we examined the effects of CTX treatment on dendritic cell (DC) subsets and the subsequent outcome on the effector and suppressive arms of adaptive immunity. In secondary lymphoid tissues, tissue-derived migratory DCs (migratory DCs), lymphoid tissue–resident DCs (resident DCs), and plasmacytoid DCs (pDCs) are well described. CTX has profound and selective cytotoxic effects on CD8+ resident DCs, but not skin-derived migratory DCs or pDCs in lymph nodes (LNs) and spleen, causing an imbalance among these DC subsets. CTX treatment increases the potency of DCs in antigen presentation and cytokine secretion, and partially inhibits the suppressor activity of Tregs. Adoptive transfer of CD8+ DCs can reconstitute this population in regional draining LNs and abrogate the immune-enhancing effects of CTX in vivo. These findings demonstrate that CTX may improve immune responses by preferentially depleting CD8+ lymphoid-resident DCs, which leads to diminished Treg suppression and enhanced effector T-cell function in vivo.
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Fan, Xiying, Bruno Moltedo, Alejandra Mendoza, Alexey N. Davydov, Mehlika B. Faire, Linas Mazutis, Roshan Sharma, Dana Pe’er, Dmitriy M. Chudakov, and Alexander Y. Rudensky. "CD49b defines functionally mature Treg cells that survey skin and vascular tissues." Journal of Experimental Medicine 215, no. 11 (October 24, 2018): 2796–814. http://dx.doi.org/10.1084/jem.20181442.
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Regulatory T (Treg) cells prevent autoimmunity by limiting immune responses and inflammation in the secondary lymphoid organs and nonlymphoid tissues. While unique subsets of Treg cells have been described in some nonlymphoid tissues, their relationship to Treg cells in secondary lymphoid organs and circulation remains unclear. Furthermore, it is possible that Treg cells from similar tissue types share largely similar properties. We have identified a short-lived effector Treg cell subset that expresses the α2 integrin, CD49b, and exhibits a unique tissue distribution, being abundant in peripheral blood, vasculature, skin, and skin-draining lymph nodes, but uncommon in the intestines and in viscera-draining lymph nodes. CD49b+ Treg cells, which display superior functionality revealed by in vitro and in vivo assays, appear to develop after multiple rounds of cell division and TCR-dependent activation. Accordingly, single-cell RNA-seq analysis placed these cells at the apex of the Treg developmental trajectory. These results shed light on the identity and development of a functionally potent subset of mature effector Treg cells that recirculate through and survey peripheral tissues.
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Vasanthakumar, Ajithkumar, Yang Liao, Peggy Teh, Maria F. Pascutti, Anna E. Oja, Alexandra L. Garnham, Renee Gloury, et al. "The TNF Receptor Superfamily-NF-κB Axis Is Critical to Maintain Effector Regulatory T Cells in Lymphoid and Non-lymphoid Tissues." Cell Reports 20, no. 12 (September 2017): 2906–20. http://dx.doi.org/10.1016/j.celrep.2017.08.068.
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Bijl, J., JW van Oostveen, M. Kreike, E. Rieger, LM van der Raaij-Helmer, JM Walboomers, G. Corte, E. Boncinelli, AJ van den Brule, and CJ Meijer. "Expression of HOXC4, HOXC5, and HOXC6 in human lymphoid cell lines, leukemias, and benign and malignant lymphoid tissue." Blood 87, no. 5 (March 1, 1996): 1737–45. http://dx.doi.org/10.1182/blood.v87.5.1737.1737.
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Abstract Besides their regulatory role in embryogenesis, homeobox (HOX) genes are expressed in a specific manner in hematopoietic cell lineages, implying a role in the molecular regulation of hematopoiesis. Some HOX C cluster genes are found to be expressed in lymphoid cells of mice and humans. Their function and expression in normal hematopoiesis are still largely unknown. We have studied the mRNA expression of HOXC4, HOXC5, and HOXC6 in several stages of lymphocyte maturation by reverse transcriptase-polymerase chain reaction (RT-PCR) and RNA in situ hybridization (RISH). We examined CD34+/CD38low and CD34+/CD38high cells obtained from normal donor bone marrow (BM), a panel of 19 lymphoid cell lines, several types of leukemias and non-Hodgkin's lymphomas (NHL), and lymphocytes isolated from tonsillar tissue and peripheral blood (PB). HOXC4 and HOXC6 were found to be expressed during maturation in B- and T-lymphoid cells. The expression of each gene was found to be initiated at different cell maturation stages. HOXC4 transcripts were present in CD34+/CD38low cells, which are thought to comprise stem cells and noncommitted progenitor cells, and in subsequent stages to terminally maturated lymphoid cells. HOXC6 expression is initiated in equivalents of prothymocyte and pre-pre-B cell stage and remains present in mature cells. However, HOXC5 is only expressed in neoplastic cell lines and in neoplastic cells of NHL, but not in CD34+ BM cells, nor in resting or activated lymphoid cells isolated from tonsil, PB, or in leukemia cells. In cell lines, weak expression of HOXC5 is initiated in equivalents of pre-B cell and common thymocyte stage and is continuously expressed in mature cell lines. Semi-quantitative RT-PCR showed that expression levels of HOXC5 were much lower than those of HOXC4 and HOXC6; furthermore an increase of expression of HOXC4, HOXC5, and HOXC6 during lymphoid cell differentiation was demonstrated. Thus, mainly mature lymphoid cell lines and neoplastic cells of NHL do express HOXC5, in contrast to the lack of expression in normal lymphoid cells and leukemias. These findings suggest involvement of HOXC5 in lymphomagenesis.
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Bijl, J., JW van Oostveen, M. Kreike, E. Rieger, LM van der Raaij-Helmer, JM Walboomers, G. Corte, E. Boncinelli, AJ van den Brule, and CJ Meijer. "Expression of HOXC4, HOXC5, and HOXC6 in human lymphoid cell lines, leukemias, and benign and malignant lymphoid tissue." Blood 87, no. 5 (March 1, 1996): 1737–45. http://dx.doi.org/10.1182/blood.v87.5.1737.bloodjournal8751737.
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Besides their regulatory role in embryogenesis, homeobox (HOX) genes are expressed in a specific manner in hematopoietic cell lineages, implying a role in the molecular regulation of hematopoiesis. Some HOX C cluster genes are found to be expressed in lymphoid cells of mice and humans. Their function and expression in normal hematopoiesis are still largely unknown. We have studied the mRNA expression of HOXC4, HOXC5, and HOXC6 in several stages of lymphocyte maturation by reverse transcriptase-polymerase chain reaction (RT-PCR) and RNA in situ hybridization (RISH). We examined CD34+/CD38low and CD34+/CD38high cells obtained from normal donor bone marrow (BM), a panel of 19 lymphoid cell lines, several types of leukemias and non-Hodgkin's lymphomas (NHL), and lymphocytes isolated from tonsillar tissue and peripheral blood (PB). HOXC4 and HOXC6 were found to be expressed during maturation in B- and T-lymphoid cells. The expression of each gene was found to be initiated at different cell maturation stages. HOXC4 transcripts were present in CD34+/CD38low cells, which are thought to comprise stem cells and noncommitted progenitor cells, and in subsequent stages to terminally maturated lymphoid cells. HOXC6 expression is initiated in equivalents of prothymocyte and pre-pre-B cell stage and remains present in mature cells. However, HOXC5 is only expressed in neoplastic cell lines and in neoplastic cells of NHL, but not in CD34+ BM cells, nor in resting or activated lymphoid cells isolated from tonsil, PB, or in leukemia cells. In cell lines, weak expression of HOXC5 is initiated in equivalents of pre-B cell and common thymocyte stage and is continuously expressed in mature cell lines. Semi-quantitative RT-PCR showed that expression levels of HOXC5 were much lower than those of HOXC4 and HOXC6; furthermore an increase of expression of HOXC4, HOXC5, and HOXC6 during lymphoid cell differentiation was demonstrated. Thus, mainly mature lymphoid cell lines and neoplastic cells of NHL do express HOXC5, in contrast to the lack of expression in normal lymphoid cells and leukemias. These findings suggest involvement of HOXC5 in lymphomagenesis.
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Zhao, Tian X., Stephen A. Newland, and Ziad Mallat. "2019 ATVB Plenary Lecture." Arteriosclerosis, Thrombosis, and Vascular Biology 40, no. 4 (April 2020): 853–64. http://dx.doi.org/10.1161/atvbaha.119.312287.
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Regulatory T cells and type-2 innate lymphoid cells represent 2 subsets of immune cells, which have been shown in preclinical models to be important in atherosclerosis and myocardial repair. Regulatory T cells play a crucial role in immune homeostasis and tolerance via their interactions with effector T cells, dendritic cells, and monocytes/macrophages. They also utilize and secrete inhibitory cytokines, including interleukin 10 and transforming growth factor β, to regulate or suppress pathogenic immune responses. Type-2 innate lymphoid cells have an important role in type-2 immune responses and tissue repair through secreting interleukins 5 and 13, as well as a variety of biological mediators and growth factors. Intriguingly, interleukin-2 has emerged as a common cytokine, which can be harnessed to upregulate both cell types, and also has important translational consequences as clinical trials are ongoing for its use in cardiovascular disease. Here, we briefly review the biology of these regulatory immune cell types, discuss the preclinical and clinical evidence for their functions in cardiovascular disease, examine the prospects for clinical translation and current ongoing trials, and finally, postulate how overlap in the mechanisms of upregulation may be leveraged in future treatments for patients.
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Nguyen, Vu H., Daisy Chang, and Robert S. Negrin. "Allogeneic Environment and Tissue Damage Provide Critical Stimuli for Regulatory T Cell Expansion and Survival In Vivo after Hematopoietic Cell Transplantation." Blood 108, no. 11 (November 16, 2006): 1731. http://dx.doi.org/10.1182/blood.v108.11.1731.1731.
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Abstract CD4+CD25+ regulatory T cells (Treg) mediate alloresponses in murine models of bone marrow transplantation (BMT), leading to protection from graft-versus-host disease (GvHD). However, in vivo migration and tissue localization of Treg during this inflammatory response remain unclear. We previously demonstrated co-localization of Treg with effector T cells (Tcon) with initial expansion in secondary lymphoid organs prior to migration into inflamed tissues in a major MHC-mismatched BMT model. To explore the stimuli for Treg proliferation, we evaluated the role of the allogeneic environment by transferring FVB donor luciferase-expressing (luc+) Treg into lethally-irradiated syngeneic recipients. Unlike the allogeneic irradiated setting where Treg expand in the presence or absence of Tcon, adoptively transferred luc+ Treg were not detected in secondary lymphoid organs of syngeneic lethally-irradiated BMT recipients by in vivo bioluminescence imaging (BLI). Syngeneic luc+ Tcon also had significantly different in vivo dynamics, with a 4 day delay and only moderate expansion in lymph nodes. Proliferation was not detected in the spleen, unlike their allogeneic Tcon counterparts, nor in the bone marrow compartments, as seen in lymphopenic models. To assess whether irradiation induced the observed in vivo dynamics of Treg in the allogeneic setting, we transferred FVB luc+ Treg or luc+ Tcon into unirradiated Balb/c Rag2−/−gamma chain (γC) −/− recipients, which lack T, B, and NK cells. After adoptive transfer into Rag2−/−γC−/− recipients, robust Tcon proliferation was observed in secondary lymphoid organs and the bone marrow compartments; however, Treg expansion was weak, and specific localization to lymphoid or nonlymphoid tissues was not observed. Treg were stimulated to localize to and expand in secondary lymphoid organs by the co-transfer of Tcon in unirradiated Rag2−/− (γC) −/− or by conditioning Rag2−/− (γC) −/− recipients with irradiation. Exogenous IL2 administration two weeks following luc+ Treg transfer into unirradiated Rag2−/− (γC) −/− recipients similarly led to localization and expansion of Treg in secondary lymphoid organs. These studies indicate the critical role of proinflammatory cytokines, such as IL2, generated either by irradiation-induced tissue damage or donor Tcon, in the expansion and localization of Treg. Differences between Tcon and Treg expansion in syngeneic or unconditioned allogeneic Rag2−/− γC−/− hosts suggest an important role of conditioning with irradiation alone or in concert with the allogeneic environment, in providing distinct signals for Tcon versus Treg activation, proliferation, and localization.
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Mortaz, Esmaeil, Saeede Amani, Sharon Mumby, Ian M. Adcock, Mehrnaz Movassaghi, Jelle Folkerts, Johan Garssen, and Gert Folkerts. "Role of Mast Cells and Type 2 Innate Lymphoid (ILC2) Cells in Lung Transplantation." Journal of Immunology Research 2018 (October 30, 2018): 1–9. http://dx.doi.org/10.1155/2018/2785971.
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The multifunctional role of mast cells (MCs) in the immune system is complex and has not fully been explored. MCs reside in tissues and mucous membranes such as the lung, digestive tract, and skin which are strategically located at interfaces with the external environment. These cells, therefore, will encounter external stimuli and pathogens. MCs modulate both the innate and the adaptive immune response in inflammatory disorders including transplantation. MCs can have pro- and anti-inflammatory functions, thereby regulating the outcome of lung transplantation through secretion of mediators that allow interaction with other cell types, particularly innate lymphoid cells (ILC2). ILC2 cells are a unique population of hematopoietic cells that coordinate the innate immune response against a variety of threats including infection, tissue damage, and homeostatic disruption. In addition, MCs can modulate alloreactive T cell responses or assist in T regulatory (Treg) cell activity. This paper outlines the current understanding of the role of MCs in lung transplantation, with a specific focus on their interaction with ILC2 cells within the engrafted organ.
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Boasso, Adriano, Monica Vaccari, Anna Hryniewicz, Dietmar Fuchs, Janos Nacsa, Valentina Cecchinato, Jan Andersson, Genoveffa Franchini, Gene M. Shearer, and Claire Chougnet. "Regulatory T-Cell Markers, Indoleamine 2,3-Dioxygenase, and Virus Levels in Spleen and Gut during Progressive Simian Immunodeficiency Virus Infection." Journal of Virology 81, no. 21 (August 22, 2007): 11593–603. http://dx.doi.org/10.1128/jvi.00760-07.
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ABSTRACT High levels of viral replication occur in gut-associated lymphoid tissue (GALT) and other lymphoid tissues (LT) since the early phase of human/simian immunodeficiency virus (HIV/SIV) infection. Regulatory T cells (Treg), a subset of immunosuppressive T cells expressing CTLA-4 and the FoxP3 transcription factor, accumulate in LT during HIV/SIV infection. Here we show that FoxP3 and CTLA-4 mRNA are increased in leukocytes from the spleens, lymph nodes (LN), and mucosal sites of chronically SIV-infected macaques with high viremia (SIVHI) compared to animals with low viremia (SIVLO). FoxP3 and CTLA-4 correlated with SIV RNA levels in tissues; SIV virus levels in the spleen, inguinal LN, mesenteric LN, colon, and jejunum directly correlated with the plasma virus level. Importantly, CTLA-4 and FoxP3 mRNA were predominantly increased in the CD25− subpopulation of leukocytes from SIVHI, further challenging the classical definition of Treg as CD4+ CD25+ T cells. Similar to CTLA-4 and FoxP3, expression of indoleamine 2,3-dioxygenase (IDO), an immunosuppressive enzyme induced by Treg in antigen-presenting cells, was increased in the spleens, mesenteric LN, colons, and jejuna from SIVHI compared to SIVLO and directly correlated to SIV RNA in the same tissues. Accordingly, plasma kynurenine/tryptophan, a marker for IDO enzymatic activity, was significantly higher in SIVHI compared to SIVLO and correlated with plasma viral levels. Increased Treg and IDO in LT of SIV-infected macaques may be the consequence of increased tissue inflammation and/or may favor virus replication during the chronic phase of SIV infection.
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Contreras, Amanda, Darin L. Wiesner, Brock Kingstad-Bakke, Woojong Lee, John P. Svaren, Bruce S. Klein, and M. Suresh. "BACH2 in TRegs Limits the Number of Adipose Tissue Regulatory T Cells and Restrains Type 2 Immunity to Fungal Allergens." Journal of Immunology Research 2022 (August 5, 2022): 1–19. http://dx.doi.org/10.1155/2022/6789055.
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FoxP3+ regulatory T cells (Tregs) are essential for self-tolerance and moderating tissue-damaging inflammation. Tregs that develop and mature in the thymus are classified as central Tregs or effector Tregs based on whether Tregs predominately inhabit secondary lymphoid organs (central Tregs) or tissues (effector Tregs). By generating mice that are conditionally deficient for Bach2 in peripheral Tregs, we have examined the role of Bach2 in regulating Treg homeostasis and effector functions. Unlike global and T cell-specific Bach2-deficient mice, Treg-specific Bach2 ablation did not result in unprovoked TH2 inflammation in the lungs. However, Bach2 deficiency in Tregs led to augmented expressions of IRF4, BATF, and GATA3 and a significant increase in the accumulation of ST2 (IL-33R)+ve effector Tregs in the spleen and visceral adipose tissue (VAT) but not in the lungs. Enhanced Bach2-deficient Treg numbers in VAT was not linked to hyperresponsiveness to exogenous IL-33 in vivo. Most strikingly, Treg-specific Bach2 deficiency resulted in enhanced fungal protease-induced Type 2 allergic inflammation in the lungs, with no detectable effects on Type 1 responses to systemic or respiratory viral infections. In summary, we ascribe vital roles for Bach2 in peripheral Tregs: as a transcriptional checkpoint to limit precocious differentiation into effector Tregs in lymphoid tissues and as a regulator of the functional program that restrains Type 2 but not Type 1 inflammation in lungs. Results presented in this manuscript implicate dysregulated Tregs in the pathogenesis of airway hypersensitivities, asthma, and other allergic disorders.
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Annacker, Oliver, Janine L. Coombes, Vivianne Malmstrom, Holm H. Uhlig, Tim Bourne, Bengt Johansson-Lindbom, William W. Agace, Christina M. Parker, and Fiona Powrie. "Essential role for CD103 in the T cell–mediated regulation of experimental colitis." Journal of Experimental Medicine 202, no. 8 (October 10, 2005): 1051–61. http://dx.doi.org/10.1084/jem.20040662.
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The integrin CD103 is highly expressed at mucosal sites, but its role in mucosal immune regulation remains poorly understood. We have analyzed the functional role of CD103 in intestinal immune regulation using the T cell transfer model of colitis. Our results show no mandatory role for CD103 expression on T cells for either the development or CD4+CD25+ regulatory T (T reg) cell–mediated control of colitis. However, wild-type CD4+CD25+ T cells were unable to prevent colitis in immune-deficient recipients lacking CD103, demonstrating a nonredundant functional role for CD103 on host cells in T reg cell–mediated intestinal immune regulation. Non–T cell expression of CD103 is restricted primarily to CD11chighMHC class IIhigh dendritic cells (DCs). This DC population is present at a high frequency in the gut-associated lymphoid tissue and appears to mediate a distinct functional role. Thus, CD103+ DCs, but not their CD103− counterparts, promoted expression of the gut-homing receptor CCR9 on T cells. Conversely, CD103− DCs promoted the differentiation of IFN-γ–producing T cells. Collectively, these data suggest that CD103+ and CD103− DCs represent functionally distinct subsets and that CD103 expression on DCs influences the balance between effector and regulatory T cell activity in the intestine.
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Yang, Kaiyong, Ana Faria, and Howard Weiner. "Sa.121. Induction of CD4+-CD25-Lap+- Regulatory T-Cells By Dendritic Cells from Gut Associated Lymphoid Tissue." Clinical Immunology 119 (January 2006): S148. http://dx.doi.org/10.1016/j.clim.2006.04.353.
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Sumitomo, Shuji, Shinichiro Nakachi, Tomohisa Okamura, Yumi Tsuchida, Rika Kato, Hirofumi Shoda, Asayo Furukawa, et al. "Identification of tonsillar CD4+CD25−LAG3+ T cells as naturally occurring IL-10-producing regulatory T cells in human lymphoid tissue." Journal of Autoimmunity 76 (January 2017): 75–84. http://dx.doi.org/10.1016/j.jaut.2016.09.005.
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Zhang, Qibo, Samuel C. Leong, Paul S. McNamara, Ayman Mubarak, Richard Malley, and Adam Finn. "Characterisation of Regulatory T Cells in Nasal Associated Lymphoid Tissue in Children: Relationships with Pneumococcal Colonization." PLoS Pathogens 7, no. 8 (August 11, 2011): e1002175. http://dx.doi.org/10.1371/journal.ppat.1002175.
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Lin, Kaifeng Lisa, Michelle L. West, James Coghill, Stephen Jones, James E. Bear, and Jonathan S. Serody. "In Vivo Assessment of T Effector, T Regulatory Cell, Dendritic Cell Interaction in Lymphoid Tissue Using Intravital Imaging During Acute GvHD." Blood 118, no. 21 (November 18, 2011): 818. http://dx.doi.org/10.1182/blood.v118.21.818.818.
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Abstract Abstract 818 Graft-versus-host disease (GvHD) is a complication that results from minor and/or major MHC incompatibilities between the donor and the recipient after hematopoietic stem cell transplantation (HSCT). Although the importance of donor T effector cells (Teffs) in inducing GvHD is well-established, the early events by which host antigen presenting cells (APCs) activate allogeneic T cells are not well described. In pathogen specific immunity, after T cells migrate to the lymph node, they initially form brief contacts with dendritic cells (DCs). This phase lasts for 6–8 hours, which is termed random-walk. Following this phase, T cells establish long-lasting arrest on DCs. At least 6 hours of stable T cell-DC interaction are required for na•ve T cells to undergo clonal expansion. After the phase of long-lasting contact, T cells start to proliferate and expand. At the same time (20∼24 hrs), their interactions with DCs become very short again. It is not clear if allogeneic T cells follow a similar tri-phasic activation process. In addition, studies on autoimmunity have shown that Tregs can prevent T cell activation by prolonged interaction with APCs. However, the mechanisms by which donor regulatory T cells (Tregs) regulate T effector responses in GvHD in lymphoid tissue has not described previously. In this study, we have used intravital microscopy to monitor the movement of donor na•ve T cells and Tregs within lymph nodes after bone marrow transplantation (BMT) in a C57BL/6 to BALB/c murine model (Figure 1A, DCs are green, T cells are red). We have found that donor na•ve T cells do not follow the triphasic activation process demonstrated by von Andrian's group for pathogen-specific transgenic T cells. Instead, a substantial minority of MHC mismatched allogeneic T cells demonstrate a diminished velocity within 4 hours of adoptive transfer. These data indicate that prolonged interactions with host DCs develop rapidly post transplant. The velocity of allogeneic T cells increased at 18 hours post BMT. Peak velocity of Teff cells occurred 24 hours post BMT, consistent with the movement pattern of activated syngeneic T cells.Figure 1.Figure 1. We have also observed that although the speed of donor Treg movement is very similar to na•ve T cell 4∼6 hours after BMT, the velocity of donor Tregs is much slower than the velocity of Teffs 18 hours post BMT. This slow speed persists even at 24 hours post BMT, indicating that Tregs form very stable contacts with host DCs. Interestingly, donor na•ve T cells move significantly faster when transplanted with Tregs at a 2:1 (T:Treg) ratio (Figure 1B), suggesting that Tregs interfere with interactions between na•ve T cells and DCs. We conclude that allogeneic na•ve T cells do not go through a random-walk phase in order to interact with host DCs early post HSCT. The transplantation of Tregs with donor T cells and bone marrow cells significantly increased the velocity of donor na•ve T cells, probably diminishing the interaction of Teff cells with DCs after BMT. We believe that the large number of APCs able to present antigen in the allogeneic setting allows for rapid activation of donor Teff cells and precludes the necessity of the random-walk phase characteristic of pathogen-specific T cells. Disclosures: No relevant conflicts of interest to declare.
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Cheng, Tsu-Yao, Jaw-Town Lin, Li-Tzong Chen, Chia-Tung Shun, Hsiu-Po Wang, Ming-Tsang Lin, Tsang-En Wang, Ann-Lii Cheng, and Ming-Shiang Wu. "Association of T-Cell Regulatory Gene Polymorphisms With Susceptibility to Gastric Mucosa-Associated Lymphoid Tissue Lymphoma." Journal of Clinical Oncology 24, no. 21 (July 20, 2006): 3483–89. http://dx.doi.org/10.1200/jco.2005.05.5434.
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Purpose Helicobacter pylori infection and host susceptibility interact to develop gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and activation of specific T cells might play a crucial role in this process. Recent investigations show that the CTLA4, CD28, and ICOS genes are located on chromosome 2q33 and their polymorphisms confer susceptibility to infectious and immune diseases through deregulation of T-cell stimulation. We aimed to determine the role of CTLA4, CD28, and ICOS polymorphisms in gastric MALT lymphoma. Patients and Methods Genotyping for CTLA4 (49 A/G, −318 C/T, and CT60 A/G), CD28 (IVS3+ 17T/C), and ICOS (c.602 A/C and c.1624C/T) was performed for 62 patients with gastric MALT lymphoma and compared with 250 unrelated healthy controls. Results H pylori infection was significantly higher in patients with gastric MALT lymphoma (90.3%) compared with controls (66.4%; P < .001). The CTLA4 −318 C/T genotype was associated with a lower risk of developing gastric MALT lymphoma (odds ratio [OR] = 0.3; P = .022), whereas CTLA4 49 G/G genotype was linked to a higher risk (OR = 4.1; P = .044). In patients with H pylori infection, CTLA4 49 G/G genotype was associated with an even higher risk (OR = 6.4; P = .047). Carriage of the tightly linked −318C –49G haplotype conferred a four-fold higher susceptibility to MALT lymphoma (OR = 4.2; P = .042). Complete remission after H pylori eradication was related to tumor stage but not to genotypes or haplotypes. Conclusion These results indicate a genetic link of CTLA4 gene polymorphisms to development of gastric MALT lymphoma and indirectly support the crucial role of host activated T cells in the MALT lymphomagenesis.
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Mittal, S., N. A. Marshall, L. Duncan, D. J. Culligan, R. N. Barker, and M. A. Vickers. "Local and Systemic Induction of an Abundant CD4+CD25+ Regulatory T Cell Population by Non-Hodgkin’s Lymphoma." Blood 110, no. 11 (November 16, 2007): 357. http://dx.doi.org/10.1182/blood.v110.11.357.357.
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Abstract Regulatory T (Treg) cells contribute to immune evasion by malignancies. To investigate their importance in non-Hodgkin’s lymphoma (NHL), we enumerated Treg cells in peripheral blood mononuclear cells (PBMC) and involved tissues from 30 newly diagnosed patients. CD25+FoxP3+CD127lowCD4+ Treg cells were increased markedly in PBMC (median=20.4% CD4 T cells, n=20) versus healthy controls (median=3.2%, n=13; p<0. 001, rank sum test) and correlated with serum lactate dehydrogenase (n=14; Rs=0.79, p <0.0001) and disease stage. The median Treg percentage of CD4 T cells from early stages (Ann Arbor stage I and II, n=4) was 12.2%, whereas it was 25.4% in advanced disease (Ann Arbor stages III, IV or bulky stage II, ≥5cm, n=10; p =0.013). We also enumerated Tr1 cells, both in peripheral blood and involved tissue samples, and again compared with healthy controls but no significant differences were noted. We documented poor proliferation of T cells with mitogen ConA and almost none with recall antigens PPD and DPT in both PBMC and involved tissue samples (n=9). T cell hyporesponsiveness was reversed by depleting CD25+ cells (n=4), or by adding anti-CTLA-4 (n=3), supporting the view that Treg cells explain the systemic immunosuppression seen in NHL. A high proportion of Treg cells was also present in involved tissues (median=38.8% CD4 T cells, n=15) versus reactive nodes (median=11.6%, n=2, p=0.02). Therefore, we tested the hypothesis that a regulatory phenotype is induced from conventional T cells within the tumor microenvironment. When autologous CD25- PBMC fractions were incubated with tumor cells from patients (n=6) in vitro, there was consistent strong induction and then expansion of cells with the CD4+CD25+FoxP3+ phenotype of classic ‘natural’ Treg cells as indicated by CFSE dilution. This induction was dependent on tumor dose and was seen when we depleted lymphoid dendritic cells from the involved tissue cell suspension using anti-CD304, or enriched the tumor cells by positive selection of CD20+ cells. This population was confirmed to be suppressive in function (n=3). We also investigated the mechanisms of this induction. Both cell-cell contact and soluble factors appeared important. In two of four cases, some induction was also noted with transwell experiments or with tumor cell conditioned supernatant, indicating that in these cases soluble factors are also involved apart from direct cell-cell contact mechanism. Reports elsewhere suggest roles for prostaglandin E2, tryptophan catabolism, IL-9 and PD-1 interaction with its ligands in inducing a Treg phenotype. Thus, we used cyclooxygenase inhibitors aspirin and sulindac, the indoleamine 2, 3-dioxygenase (IDO) inhibitor 1-methyl tryptophan (1MT), anti-IL-9 receptor antibody and blocking anti-PDL-1 or anti-PDL-2 antibodies in four samples. None of these reagents inhibited Treg induction apart from one case where both anti-PDL-1 and anti-PDL-2 blocking antibodies inhibited Treg induction. We conclude that NHL cells are powerful inducers of Treg cells, which may represent a new therapeutic target.
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Wang, Shuang, Xueyang Zou, Yi Zhang, Xiaoya Wang, Wei Yang, and Yi Li. "The Generation and Regulation of Tissue-Resident Tregs and Their Role in Autoimmune Diseases." Journal of Immunology Research 2020 (November 19, 2020): 1–13. http://dx.doi.org/10.1155/2020/8815280.
Full textAbstract:
Regulatory T cells (Tregs), as an important subset of T cells, play an important role in maintaining body homeostasis by regulating immune responses and preventing autoimmune diseases. In-depth research finds that Tregs have strong instability and plasticity, and according to their developmental origin, Tregs can be classified into thymic-derived Tregs (tTregs), endogenous-induced Tregs (pTregs), which are produced by antigen-stimulated T cells in the periphery in vivo, and induced Tregs (iTregs), which differentiate from naïve T cells in vitro. In recent years, studies have found that Tregs are divided into lymphatic and tissue-resident Tregs according to their location. Research on the generation and function of lymphoid Tregs has been more comprehensive and thorough, but the role of tissue Tregs is still in the exploratory stage, and it has become a research hot spot. In this review, we discuss the instability and plasticity of Tregs and the latest developments of tissue-resident Tregs in the field of biology, including adipose tissue, colon, skeletal muscle, and other Tregs that have been recently discovered as well as their production, regulation, and function in specific tissues and their role in the pathogenesis of autoimmune diseases.
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Li, Chaoran, Andrés R. Muñoz-Rojas, Gang Wang, Alexander O. Mann, Christophe Benoist, and Diane Mathis. "PPARγ marks splenic precursors of multiple nonlymphoid-tissue Treg compartments." Proceedings of the National Academy of Sciences 118, no. 13 (March 22, 2021): e2025197118. http://dx.doi.org/10.1073/pnas.2025197118.
Full textAbstract:
Foxp3+CD4+ regulatory T cells (Tregs) regulate most types of immune response as well as several processes important for tissue homeostasis, for example, metabolism and repair. Dedicated Treg compartments—with distinct transcriptomes, T cell receptor repertoires, and growth/survival factor dependencies—have been identified in several nonlymphoid tissues. These Tregs are specifically adapted to function and operate in their home tissue—When, where, and how do they take on their specialized characteristics? We recently reported that a splenic Treg population expressing low levels of the transcription factor PPARγ (peroxisome proliferator-activated receptor gamma) contains precursors of Tregs residing in visceral adipose tissue. This finding made sense given that PPARγ, the “master regulator” of adipocyte differentiation, is required for the accumulation and function of Tregs in visceral adipose tissue but not in lymphoid tissues. Here we use single-cell RNA sequencing, single-cell Tcra and Tcrb sequencing, and adoptive-transfer experiments to show that, unexpectedly, the splenic PPARγlo Treg population is transcriptionally heterogeneous and engenders Tregs in multiple nonlymphoid tissues beyond visceral adipose tissue, such as skin and liver. The existence of a general pool of splenic precursors for nonlymphoid-tissue Tregs opens possibilities for regulating their emergence experimentally or therapeutically.
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Zafar, Shazia, Sathish Srinivasan, and Zafar Nawaz. "E6-Associated Protein (E6-AP): A Potential Tumor Suppressor Protein for Non-Hodgkin Lymphoma." Blood 108, no. 11 (November 16, 2006): 4336. http://dx.doi.org/10.1182/blood.v108.11.4336.4336.
Full textAbstract:
Abstract Over the past decade considerable progress has been made in cloning and characterization of potential tumor suppressor genes. Tumor suppressors have a repressive effect on the regulation of the cell cycle or promote apoptosis and sometimes do both. The function of tumor suppressor proteins fall into several categories, tumor suppressor genes are presumed to encode negative regulator of proliferation and inhibit mitotic activity. Loss of tumor suppressor protein or function of a tumor suppressor protein has been shown to be associated with the cancer formation. Continued investigation into the biochemical and cell biological functions of the tumor suppressor is critical to elucidate the mechanisms by which they normally inhibit proliferation/tumor development and to provide a molecular explanation for their frequent inactivation in cancer. Our laboratory has previously shown that the expression of E6-associated protein (E6-AP), which is an E3 ubiquitin-protein ligase and a coactivator of nuclear hormone receptors, is significantly reduced in human cancers having epithelial cell origin such as breast cancer. In this prospective study, we want to extend our observation to the cancers originating from lymphoid tissue. Non-Hodgkin lymphoma is a cancer of lymphoid tissue. The main cell type found in lymphoid tissue is the lymphocyte. The 2 main types of lymphocytes are B-lymphocytes (B-cells) and T-lymphocytes (T-cells). B-cell lymphomas are much more common than T-cell lymphomas. In the U. S., 85% of all cases of non-Hodgkin lymphoma come from B lymphocytes (B-cell) and 15% from T lymphocytes (T-cell). We performed immunohistochemistry analysis to investigate the expression pattern of E6-AP in normal lymph nodes and lymphoid tumors. Tissue micro arrays representing samples from 60 different patients were analyzed in this study. Our analysis suggest that on an average there was about 55 % reduction in E6-AP protein levels in B-cell lymphomas (P =0.0001) and 98.5 % reduction in E6-AP levels in T-cell lymphomas (P =0.0002) compared to normal lymph node. Based on our previous studies in breast and prostate tumors and considering our current finding of reduced/loss of E6-AP in lymphoid tumors, we propose that E6-AP may act as a potential tumor suppressor protein. This proposed idea is consistent with our in vivo data generated from E6-AP null mice which shows that the number of B- and T-cells are significantly increased in spleen compared to normal wild-type animals. Taken together our data establish the role of E6-AP as a potential growth and tumor suppressor protein.
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Ronin, Emilie, Charlotte Pouchy, Maryam Khosravi, Morgane Hilaire, Sylvie Grégoire, Armanda Casrouge, Sahar Kassem, et al. "Tissue-restricted control of established central nervous system autoimmunity by TNF receptor 2–expressing Treg cells." Proceedings of the National Academy of Sciences 118, no. 13 (March 25, 2021): e2014043118. http://dx.doi.org/10.1073/pnas.2014043118.
Full textAbstract:
CD4+Foxp3+ regulatory T (Treg) cells are central modulators of autoimmune diseases. However, the timing and location of Treg cell–mediated suppression of tissue-specific autoimmunity remain undefined. Here, we addressed these questions by investigating the role of tumor necrosis factor (TNF) receptor 2 (TNFR2) signaling in Treg cells during experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. We found that TNFR2-expressing Treg cells were critical to suppress EAE at peak disease in the central nervous system but had no impact on T cell priming in lymphoid tissues at disease onset. Mechanistically, TNFR2 signaling maintained functional Treg cells with sustained expression of CTLA-4 and Blimp-1, allowing active suppression of pathogenic T cells in the inflamed central nervous system. This late effect of Treg cells was further confirmed by treating mice with TNF and TNFR2 agonists and antagonists. Our findings show that endogenous Treg cells specifically suppress an autoimmune disease by acting in the target tissue during overt inflammation. Moreover, they bring a mechanistic insight to some of the adverse effects of anti-TNF therapy in patients.
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Cho, Jun, Wilson Kuswanto, Christophe Benoist, and Diane Mathis. "T cell receptor specificity drives accumulation of a reparative population of regulatory T cells within acutely injured skeletal muscle." Proceedings of the National Academy of Sciences 116, no. 52 (December 10, 2019): 26727–33. http://dx.doi.org/10.1073/pnas.1914848116.
Full textAbstract:
Foxp3+CD4+regulatory T cells (Tregs) play important roles in controlling both homeostatic processes and immune responses at the tissue and organismal levels. For example, Tregs promote muscle regeneration in acute or chronic injury models by direct effects on local muscle progenitor cells, as well as on infiltrating inflammatory cells. Muscle Tregs have a transcriptome, a T cell receptor (TCR) repertoire, and effector capabilities distinct from those of classical, lymphoid-organ Tregs, but it has proven difficult to study the provenance and functions of these unique features due to the rarity of muscle Tregs and their fragility on isolation. Here, we attempted to sidestep these hindrances by generating, characterizing, and employing a line of mice carrying rearranged transgenes encoding the TCRα and TCRβ chains from a Treg clone rapidly and specifically expanded within acutely injured hindlimb muscle of young mice. Tregs displaying the transgene-encoded TCR preferentially accumulated in injured hindlimb muscle in a TCR-dependent manner both in the straight transgenic model and in adoptive-transfer systems; non-Treg CD4+T cells expressing the same TCR did not specifically localize in injured muscle. The definitive muscle-Treg transcriptome was not established until the transgenic Tregs inhabited muscle. When crossed onto themdxmodel of Duchenne muscular dystrophy, the muscle-Treg TCR transgenes drove enhanced accumulation of Tregs in hindlimb muscles and improved muscle regeneration. These findings invoke the possibility of harnessing muscle Tregs or their TCRs for treatment of skeletal muscle pathologies.
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Greenberg, Steven A., Jack L. Pinkus, Sek Won Kong, Clare Baecher-Allan, Anthony A. Amato, and David M. Dorfman. "Highly differentiated cytotoxic T cells in inclusion body myositis." Brain 142, no. 9 (July 20, 2019): 2590–604. http://dx.doi.org/10.1093/brain/awz207.
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Abstract Inclusion body myositis is a late onset treatment-refractory autoimmune disease of skeletal muscle associated with a blood autoantibody (anti-cN1A), an HLA autoimmune haplotype, and muscle pathology characterized by cytotoxic CD8+ T cell destruction of myofibres. Here, we report on translational studies of inclusion body myositis patient muscle compared with a diverse set of other muscle disease samples. Using available microarray data on 411 muscle samples from patients with inclusion body myositis (n = 40), other muscle diseases (n = 265), and without neuromuscular disease (normal, n = 106), we identified a signature of T-cell cytotoxicity in inclusion body myositis muscle coupled with a signature of highly differentiated CD8 T-cell effector memory and terminally differentiated effector cells. Further, we examined killer cell lectin-like receptor G1 (KLRG1) as a marker of this population of cells, demonstrated the correlation of KLRG1 gene expression with lymphocyte cytotoxicity across 28 870 human tissue samples, and identified the presence of KLRG1 on pathogenic inclusion body myositis muscle invading T cells and an increase in KLRG1 expressing T cells in inclusion body myositis blood. We examined inclusion body myositis muscle T-cell proliferation by Ki67 immunohistochemistry demonstrating that diseased muscle-invading T cells are minimally or non-proliferative, in accordance with known properties of highly differentiated or terminally differentiated T cells. We found low expression of KLRG1 on infection-protective human lymphoid tissue central memory T cells and autoimmune-protective human blood regulatory T cells. Targeting highly differentiated cytotoxic T cells could be a favourable approach to treatment of inclusion body myositis.