scholarly journals The Role of Gamma Delta T Cells in Autoimmune Rheumatic Diseases

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 462 ◽  
Author(s):  
Ilan Bank
Keyword(s):  
T Cells ◽  
T Cell ◽  
Rheumatic Diseases ◽  
Lupus Erythematosus ◽  
Cell Biology ◽  
Γδ T Cells ◽  
Immune Functions ◽  
Autoimmune Rheumatic Diseases ◽  
New Therapeutic Approaches

Autoimmune rheumatic diseases (ARDs), affecting ~1–1.5% of all humans, are associated with considerable life long morbidity and early mortality. Early studies in the 1990s showed numerical changes of the recently discovered γδ T cells in the peripheral blood and in affected tissues of patients with a variety of ARDs, kindling interest in their role in the immuno-pathogenesis of these chronic inflammatory conditions. Indeed, later studies applied rapid developments in the understanding of γδ T cell biology, including antigens recognized by γδ T cells, their developmental programs, states of activation, and cytokine production profiles, to analyze their contribution to the pathological immune response in these disorders. Here we review the published studies addressing the role of γδ T in the major autoimmune rheumatic diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, systemic lupus erythematosus and scleroderma, and animal models thereof. Due to their unique properties spanning adaptive and innate immune functions, the ever deeper understanding of this unique T cell population is shedding new light on the pathogenesis of, while potentially enabling new therapeutic approaches to, these diseases.

scholarly journals T Cell Receptor Specificity Is Critical for the Development of Epidermal γδ T Cells

2001 ◽  
Vol 194 (10) ◽  
pp. 1473-1483 ◽  
Author(s):  
Isabel Ferrero ◽  
Anne Wilson ◽  
Friedrich Beermann ◽  
Werner Held ◽  
H. Robson MacDonald
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Biology ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Wild Type ◽  
Normal Numbers ◽  
T Cell Biology

A particular feature of γδ T cell biology is that cells expressing T cell receptor (TCR) using specific Vγ/Vδ segments are localized in distinct epithelial sites, e.g., in mouse epidermis nearly all γδ T cells express Vγ3/Vδ1. These cells, referred to as dendritic epidermal T cells (DETC) originate from fetal Vγ3+ thymocytes. The role of γδ TCR specificity in DETC's migration/localization to the skin has remained controversial. To address this issue we have generated transgenic (Tg) mice expressing a TCR δ chain (Vδ6.3-Dδ1-Dδ2-Jδ1-Cδ), which can pair with Vγ3 in fetal thymocytes but is not normally expressed by DETC. In wild-type (wt) Vδ6.3Tg mice DETC were present and virtually all of them express Vδ6.3. However, DETC were absent in TCR-δ−/− Vδ6.3Tg mice, despite the fact that Vδ6.3Tg γδ T cells were present in normal numbers in other lymphoid and nonlymphoid tissues. In wt Vδ6.3Tg mice, a high proportion of in-frame Vδ1 transcripts were found in DETC, suggesting that the expression of an endogenous TCR-δ (most probably Vδ1) was required for the development of Vδ6.3+ epidermal γδ T cells. Collectively our data demonstrate that TCR specificity is essential for the development of γδ T cells in the epidermis. Moreover, they show that the TCR-δ locus is not allelically excluded.

scholarly journals Circulating TCR γδ Cells in the Patients with Systemic Lupus Erythematosus

1999 ◽  
Vol 8 (6) ◽  
pp. 305-312 ◽  
Author(s):  
Ewa Robak ◽  
Jerzy Z. Błoński ◽  
Jacek Bartkowiak ◽  
Hanna Niewiadomska ◽  
Anna Sysa-Jędrzejowska ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Lupus Erythematosus ◽  
Γδ T Cells ◽  
Inactive Disease ◽  
Control Group ◽  
Systemic Lupus

Systemic lupus erythematosus (SLE) is a disorder with a wide range of immunological abnormalities. The results of the studies undertaken in the last decade indicated that SLE pathogenesis was mainly connected with the breakdown of the activation control of B and T cells, generating humoral or cell-mediated responses against several self-antigens of affected cells. The last studies demonstrate that the role of γδ T lymphocytes in autoimmune diseases can be especially important. Flow cytometry techniques were used to investigate the number and percentage of TCR γδ T cells and their most frequent subtypes in peripheral blood of 32 patients with SLE and 16 healthy volunteers. We also correlated TCR γδ cells number with the level of T CD3+, T CD4+, T CD8+, and NK (CD16) cells (cytometric measurements) and SLE activity (on the basis of clinical investigations). Our studies were preliminary attempts to evaluate the role of that minor T cell subpopulation in SLE. Absolute numbers of cells expressing γδ TCR in most SLE blood specimens were significantly lower than in the control group (P<0.006). However, since the level of total T cell population was also decreased in the case of SLE, the mean values of the percentage γδ T cells of pan T lymphocytes were almost the same in both analysed populations (7.1% vs 6.3%, respectively). In contrast to Vδ2+ and Vγ9+ subtypes of pan γδ T cells, Vδ3+ T cells number was higher in SLE patients (20×10 cells/μl) than in healthy control group (2×2 cells/μl) (P=0.001). However, we found no differences between the numbers of pan γδ T lymphocytes and studied their subtypes in the patients with active and inactive disease. These cell subpopulations were doubled in the treated patients with immunosuppressive agents in comparison with untreated ones; however, data were not statistically significant. Our study indicated that Vδ3+ subtype of γδ T cells seems to be involved in SLE pathogenesis; however, we accept the idea that the autoimmunity does not develop from a single abnormality, but rather from a number of different events.

scholarly journals The role of unconventional T cells in COVID-19

2021 ◽  
Author(s):  
Kristen Orumaa ◽  
Margaret R. Dunne
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Treatment Strategies ◽  
Γδ T Cells ◽  
Protective Role ◽  
T Cell Subsets ◽  
Viral Immunity ◽  
Mait Cells

AbstractCOVID-19 is a respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first documented in late 2019, but within months, a worldwide pandemic was declared due to the easily transmissible nature of the virus. Research to date on the immune response to SARS-CoV-2 has focused largely on conventional B and T lymphocytes. This review examines the emerging role of unconventional T cell subsets, including γδ T cells, invariant natural killer T (iNKT) cells and mucosal associated invariant T (MAIT) cells in human SARS-CoV-2 infection.Some of these T cell subsets have been shown to play protective roles in anti-viral immunity by suppressing viral replication and opsonising virions of SARS-CoV. Here, we explore whether unconventional T cells play a protective role in SARS-CoV-2 infection as well. Unconventional T cells are already under investigation as cell-based immunotherapies for cancer. We discuss the potential use of these cells as therapeutic agents in the COVID-19 setting. Due to the rapidly evolving situation presented by COVID-19, there is an urgent need to understand the pathogenesis of this disease and the mechanisms underlying its immune response. Through this, we may be able to better help those with severe cases and lower the mortality rate by devising more effective vaccines and novel treatment strategies.

scholarly journals T cell–specific STAT3 deficiency abrogates lupus nephritis

Lupus ◽  
2019 ◽  
Vol 28 (12) ◽  
pp. 1468-1472 ◽  
Author(s):  
N Yoshida ◽  
F He ◽  
V C Kyttaris
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Cell Responses ◽  
Cytokines And Chemokines ◽  
Novel Approach ◽  
Cell Tissue ◽  
External Stimuli

Signal transducer and activator of transcription (STAT) 3 is a regulator of T-cell responses to external stimuli, such as pro-inflammatory cytokines and chemokines. We have previously shown that STAT3 is activated (phosphorylated) at high levels in systemic lupus erythematosus (SLE) T cells and mediates chemokine-induced migration and T:B cell interactions. Stattic, a small molecular STAT3 inhibitor, can partially ameliorate lupus nephritis in mice. To understand the role of STAT3 better in T-cell pathophysiology in lupus nephritis and its potential as a treatment target, we silenced its expression in T cells using a cd4-driven CRE-Flox model. We found that lupus-prone mice that do not express STAT3 in T cells did not develop lymphadenopathy, splenomegaly, or glomerulonephritis. Moreover, the production of anti-dsDNA antibodies was decreased in these mice compared to controls. To dissect the mechanism, we also used a nephrotoxic serum model of nephritis. In this model, T cell–specific silencing of STAT3 resulted in amelioration of nephrotoxic serum-induced kidney damage. Taken together, our results suggest that in mouse models of autoimmune nephritis, T cell–specific silencing of STAT3 can hamper their ability to help B cells to produce autoantibodies and induce cell tissue infiltration. We propose that STAT3 inhibition in T cells represents a novel approach in the treatment of SLE and lupus nephritis in particular.

scholarly journals Regulation and Functions of Protumoral Unconventional T Cells in Solid Tumors

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3578
Author(s):  
Emilie Barsac ◽  
Carolina de Amat Herbozo ◽  
Loïc Gonzalez ◽  
Thomas Baranek ◽  
Thierry Mallevaey ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Immunity ◽  
Cell Biology ◽  
Therapeutic Potential ◽  
Γδ T Cells ◽  
Feasibility Studies ◽  
T Cell Subsets ◽  
Mait Cells ◽  
Nonpeptide Antigens

The vast majority of studies on T cell biology in tumor immunity have focused on peptide-reactive conventional T cells that are restricted to polymorphic major histocompatibility complex molecules. However, emerging evidence indicated that unconventional T cells, including γδ T cells, natural killer T (NKT) cells and mucosal-associated invariant T (MAIT) cells are also involved in tumor immunity. Unconventional T cells span the innate–adaptive continuum and possess the unique ability to rapidly react to nonpeptide antigens via their conserved T cell receptors (TCRs) and/or to activating cytokines to orchestrate many aspects of the immune response. Since unconventional T cell lineages comprise discrete functional subsets, they can mediate both anti- and protumoral activities. Here, we review the current understanding of the functions and regulatory mechanisms of protumoral unconventional T cell subsets in the tumor environment. We also discuss the therapeutic potential of these deleterious subsets in solid cancers and why further feasibility studies are warranted.

T Lymphocytes: The “Cellular” Arm of Acquired Immunity in the Peritoneum

2006 ◽  
Vol 26 (4) ◽  
pp. 438-448 ◽  
Author(s):  
Amir Glik ◽  
Amos Douvdevani
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Antigen Presentation ◽  
Cell Population ◽  
Cell Biology ◽  
Specific Antigen ◽  
Acquired Immunity ◽  
Polymorphonuclear Cells

T cells are an important part of the acquired immune response and target specific antigen with their T cell receptor. The peritoneum is a special milieu within which T cells react. We describe briefly the anatomy important for T cell function. T cell biology including antigen presentation, T cell activation, and the different T cell subpopulations are reviewed. We also define innate and acquired immunity and describe the role of polymorphonuclear cells and peritoneal mesothelial cells in the regulation of leukocyte population recruitment during peritonitis. We focus particularly on peritoneal lymphocytes and compare them to the regular lymphocyte populations in the circulation. We illustrate the role of PMCs in antigen presentation and discuss the changes of CD4+ helper T cell subtypes (Th1 and Th2) during peritoneal dialysis. The role of CD8+ cytotoxic T lymphocytes and their possible destructive role for the peritoneal membrane modified by advanced glycation end products are discussed. Polymorphonuclear cells play an important role in the regulation of inflammation and immunity. We describe their possible role in supporting T cells and particularly for generating memory CD8+ T cells by secretion of interleukin-15, a potent T cell growth factor. Light is shed on γδ T cells, a special T cell population that is able to recognize antigens without the restriction of antigen presentation. We end our review with a description of regulatory T cells. This cell population is extremely important in preventing autoimmunity and in the regulation of acquired immunity.

scholarly journals Critical role of host γδ T cells in experimental acute graft-versus-host disease

Blood ◽  
2005 ◽  
Vol 106 (2) ◽  
pp. 749-755 ◽  
Author(s):  
Yoshinobu Maeda ◽  
Pavan Reddy ◽  
Kathleen P. Lowler ◽  
Chen Liu ◽  
Dennis Keith Bishop ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Critical Role ◽  
Γδ T Cells ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Tnf Α

Abstract γδ T cells localize to target tissues of graft-versus-host disease (GVHD) and therefore we investigated the role of host γδ T cells in the pathogenesis of acute GVHD in several well-characterized allogeneic bone marrow transplantation (BMT) models. Depletion of host γδ T cells in wild-type (wt) B6 recipients by administration of anti-T-cell receptor (TCR) γδ monoclonal antibody reduced GVHD, and γδ T-cell-deficient (γδ-/-) BM transplant recipients experienced markedly improved survival compared with normal controls (63% vs 10%, P &lt; .001). γδ T cells were responsible for this difference because reconstitution of γδ-/- recipients with γδ T cells restored GVHD mortality. γδ-/- recipients showed decreased serum levels of tumor necrosis factor α (TNF-α), less GVHD histopathologic damage, and reduced donor T-cell expansion. Mechanistic analysis of this phenomenon demonstrated that dendritic cells (DCs) from γδ-/- recipients exhibited less allostimulatory capacity compared to wt DCs after irradiation. Normal DCs derived from BM caused greater allogeneic T-cell proliferation when cocultured with γδ T cells than DCs cocultured with medium alone. This enhancement did not depend on interferon γ (IFN-γ), TNF-α, or CD40 ligand but did depend on cell-to-cell contact. These data demonstrated that the host γδ T cells exacerbate GVHD by enhancing the allostimulatory capacity of host antigen-presenting cells. (Blood. 2005;106:749-755)

scholarly journals Donor γδ T Lymphocytes Promote Allogeneic Engraftment Across the Major Histocompatibility Barrier in Mice

Blood ◽  
1997 ◽  
Vol 89 (3) ◽  
pp. 1100-1109 ◽  
Author(s):  
William R. Drobyski ◽  
David Majewski
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Marrow Graft ◽  
Hematopoietic Reconstitution ◽  
Donor T Cells ◽  
Αβ T Cells

Abstract T cells that express the αβ T-cell receptor are thought to be the T-cell population primarily responsible for facilitating alloengraftment. The role of γδ+ T cells that comprise only a minority of mature T cells in promoting allogeneic engraftment, however, has not been extensively studied. The purpose of this study was to determine whether γδ T cells were capable of facilitating alloengraftment in murine recipients of major histocompatibility complex-mismatched marrow grafts. We developed a model where engraftment of C57BL/6 × 129/F2 (H-2b) marrow in sublethally irradiated (800 cGy) recipients (AKR/J, H-2k) is dependent on the presence of mature donor T cells in the marrow graft. In this model, donor T-cell engraftment was significantly augmented by as few as 1 × 105 αβ T cells. The role of γδ T cells was then investigated using transgenic donors (C57BL/6 × 129 background) in which a portion of the T-cell receptor–β chain gene was deleted by gene targeting so that these mice lack αβ T cells. Addition of 10 × 106 naive γδ T cells to T-cell depleted marrow grafts was required to significantly increase alloengraftment, although donor T cells averaged <50% of total splenic T cells. To determine whether higher doses of γδ T cells would improve donor engraftment and eradicate residual host T cells, γδ T cells were ex vivo expanded with a γδ T-cell–specific monoclonal antibody and interleukin-2 and then transplanted into irradiated recipients. Transplantation of ≥ 160 × 106 activated γδ T cells was necessary to consistently and significantly augment donor cell chimerism and enhance hematopoietic reconstitution when compared to control mice, but host T cells persisted in these chimeras. Addition of 2.5 × 104 mature αβ T cells, which alone were incapable of facilitating engraftment, to T-cell depleted marrow grafts containing 160 × 106 activated γδ T cells resulted in long-term (<100 day) complete donor engraftment, indicating that limiting numbers of αβ T cells were required in the marrow graft for the eradication of residual host T cells. Using serial weight curves and B-cell reconstitution as end points, clinically significant graft-versus-host disease was not observed in these chimeras under these experimental conditions. These data show that, whereas less potent than αβ T cells, γδ T cells are able to promote engraftment and enhance hematopoietic reconstitution in allogeneic marrow transplant recipients.

scholarly journals The Unknown Unknowns: Recovering Gamma-Delta T Cells for Control of Human Immunodeficiency Virus (HIV)

Viruses ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1455
Author(s):  
Shivkumar Biradar ◽  
Michael T. Lotze ◽  
Robbie B. Mailliard
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Cell Biology ◽  
Γδ T Cells ◽  
Γδ T Cell ◽  
T Cell Biology ◽  
Immunodeficiency Virus

Recent advances in γδ T cell biology have focused on the unique attributes of these cells and their role in regulating innate and adaptive immunity, promoting tissue homeostasis, and providing resistance to various disorders. Numerous bacterial and viral pathogens, including human immunodeficiency virus-1 (HIV), greatly alter the composition of γδ T cells in vivo. Despite the effectiveness of antiretroviral therapy (ART) in controlling HIV and restoring health in those affected, γδ T cells are dramatically impacted during HIV infection and fail to reconstitute to normal levels in HIV-infected individuals during ART for reasons that are not clearly understood. Importantly, their role in controlling HIV infection, and the implications of their failure to rebound during ART are also largely unknown and understudied. Here, we review important aspects of human γδ T cell biology, the effector and immunomodulatory properties of these cells, their prevalence and function in HIV, and their immunotherapeutic potential.

scholarly journals Neuronal-Activated ILC2s Promote IL-17A Production in Lung γδ T Cells During Sepsis

2021 ◽  
Vol 12 ◽  
Author(s):  
Weiwei Chen ◽  
Dengming Lai ◽  
Yuehua Li ◽  
Xueke Wang ◽  
Yihang Pan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Expansion ◽  
Cecal Ligation ◽  
Γδ T Cells ◽  
Lymphoid Cells ◽  
Γδ T Cell ◽  
Neuronal Regulation ◽  
T Cell Expansion

BackgroundStudies have revealed important roles for IL-17A in the development of acute lung injury (ALI) following sepsis. However, the mechanism underlying the regulation of lung IL-17A remains to be fully addressed. Recent studies suggested the effect of neuromedin U (NMU) on immune cell activation and the role of group 2 innate lymphoid cells (ILC2s) in the modulation of IL-17A production. We aimed to gain in-depth insight into the mechanism underlying sepsis-induced lung IL-17A production, particularly, the role of NMU in mediating neuronal regulation of ILC2s and IL-17A-producing γδ T cells activation in sepsis.MethodsWild type mice were subjected to cecal ligation and puncture (CLP) to induce sepsis with or without intraperitoneal injection of NMU. The levels of ILC2s, γδ T cells, IL-17A, NMU and NMU receptor 1 (NMUR1) in the lung were then measured. In order to determine the role of NMU signaling in ILC2 activation and the role of ILC2-released IL-9 in ILC2-γδ T cell interaction, ILC2s were sorted, and the genes of nmur1 and il9 in the ILC2s were knocked down using CRISPR/Cas9. The genetically manipulated ILC2s were then co-cultured with lung γδ T cells, and the levels of IL-17A from co-culture systems were measured.ResultsIn septic mice, the levels of NMU, IL-17A, ILC2s, and IL-17A-producing γδ T cells in the lung are significantly increased, and the expression of NMUR1 in ILC2s is increased as well. Exogenous NMU further augments these increases. The main source of IL-17A in response to CLP is γδ T cells, and lung nmur1 is specifically expressed in ILC2s. In vitro co-culture of ILC2s and γδ T cells leads to increased number of γδ T cells and higher production of IL-17A from γδ T cells, and these alterations are further augmented by septic treatment and exogenous NMU. Genetic knockdown of nmur1 or il9 in ILC2s attenuated the upregulation of γδ T cells and IL-17A production.ConclusionIn sepsis, NMU acting through NMUR1 in lung ILC2s initiates the ILC2 activation, which, in turn, promote IL-17A-producing γδ T cell expansion and secretion of IL-17A. ILC2-derived IL-9 plays an important role in mediating γδ T cell expansion and IL-17A production. This study explores a new mechanism underlying neuronal regulation of innate immunity in sepsis.

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