scholarly journals Regulatory Role of CD4+ T Cells in Myocarditis

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Daria Vdovenko ◽  
Urs Eriksson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Young Patients ◽  
Peripheral Tolerance ◽  
T Cell Subsets ◽  
High Plasticity ◽  
Clonal Deletion ◽  
Effector T Cell

Myocarditis is an important cause of heart failure in young patients. Autoreactive, most often, infection-triggered CD4+ T cells were confirmed to be critical for myocarditis induction. Due to a defect in clonal deletion of heart-reactive CD4+ T cells in the thymus of mice and humans, significant numbers of heart-specific autoreactive CD4+ T cells circulate in the blood. Normally, regulatory T cells maintain peripheral tolerance and prevent spontaneous myocarditis development. In the presence of tissue damage and innate immune activation, however, activated self-antigen-loaded dendritic cells promote CD4+ effector T cell expansion and myocarditis. So far, a direct pathogenic role has been described for both activated Th17 and Th1 effector CD4+ T cell subsets, though Th1 effector T cell-derived interferon-gamma was shown to limit myocarditis severity and prevent transition to inflammatory dilated cardiomyopathy. Interestingly, recent observations point out that various CD4+ T cell subsets demonstrate high plasticity in maintaining immune homeostasis and modulating disease phenotypes in myocarditis. These subsets include Th1 and Th17 effector cells and regulatory T cells, despite the fact that there are still sparse and controversial data on the specific role of FOXP3-expressing Treg in myocarditis. Understanding the specific roles of these T cell populations at different stages of the disease progression might provide a key for the development of successful therapeutic strategies.

Double Negative T Cells Influence TCR VB Variablity to Induce Allotolerance.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 759-759
Author(s):  
Zachariah A. McIver ◽  
Marcin Wlodarski ◽  
Jennifer Powers ◽  
Christine O’Keefe ◽  
Tao Jin ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Peripheral Tolerance ◽  
Double Negative ◽  
Clonal Deletion ◽  
Tcr Repertoire ◽  
Double Negative T Cells

Abstract Immune alloresponsiveness following allogeneic HSCT is influenced by the dynamics of immune reconstitution and development of allotolerance. In general, tolerance is induced by thymic clonal deletion (central) and apoptosis or suppression of alloresponsive lymphocytes by regulatory T cells in the periphery. We have recently demonstrated that the size of the TCR repertoire within the CD4 and CD8 compartments can be assessed using VB spectrum by flow cytometry, and expansions/losses of individual TCR VB families can be used as a surrogate marker of TCR variability. (Exp. Hem.32: 1010–1022; Br. J. Haematol.129:411–419). Additionally, regulatory T cells can also impact the clonal contractions and expansions within the TCR VB repertoire. Various types of regulatory T cells have been described including CD4+CD25+, CD8+, NK T−cells, and CD3+CD4/CD8− double negative T cells (DN Tregs). In our current study we investigated the role of DN Tregs on the restoration of immune repertoire diversity. We hypothesized that alloresponsiveness clinically detected as a manifestation of GvHD may be associated with oligoclonal T−cell expansions, and in this context decreased numbers of regulatory T cells suggest deficient tolerizing function by regulatory T cells including DN Tregs. Here we studied a cohort of 60 HSCT recipients (AML, CML, CLL, NHL, AA, and PV), of which 25 patients received matched unrelated donor grafts and 35 received matched sibling donor grafts. Blood was sampled between 2003–2006 at monthly intervals after HSCT, and flow cytometry for TCR repertoire in CD4 and CD8 cells as well as the numbers of DN cells were recorded. Additionally, separate samples were collected for measurement of chimerism and were included in analysis when donor lymphoid chimerism was > 60%. A subset analysis was performed based on the presence/absence of GvHD. For the 27/60 (45%) patients with episodes of GvHD, results were obtained at the time of diagnosis of GvHD (grade > 2), while for patients in whom notable GvHD was not captured, the steady−state values at corresponding times were used for analysis. For all patients serial evaluations were available. For the purpose of this study, significant VB expansions/contractions were defined as +/− 2 standard deviation over the average VB family size. Using Cox proportional hazards analysis to identify univariate risk factors for GVHD, CD8 VB TCR contractions > 14 VB families (58.3% contraction of entire CD4 VB repertoire) constituted a strong indicator for increased risk (HR=7.61, p=0.011). This observation is consistent with the fact that oligoclonality of alloreactive T cell clones is frequently accompanied by a significant contraction/loss of remaining VB families and may herald heightened alloresponsiveness as a manifestation of GvHD. Estimation for correlation by Pearson’s correlation coefficient also demonstrated that percentage of DN cells strongly correlated with a normalization of CD4 VB TCR repertoire (lower number of expansions; N=57, R= −0.51, p=0.027), supporting our hypothesis that DN cells participate in peripheral tolerance and suppress proliferative, alloresponsive CD4 clones. In summary, our results further characterize TCR variability post HSCT and define the role of DN cells in the induction of allotolerance.

scholarly journals An imbalance of esophageal effector and regulatory T cell subsets in experimental eosinophilic esophagitis in mice

2009 ◽  
Vol 297 (3) ◽  
pp. G550-G558 ◽  
Author(s):  
Xiang Zhu ◽  
Meiqin Wang ◽  
Caleb H. Crump ◽  
Anil Mishra
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Eosinophilic Esophagitis ◽  
Critical Role ◽  
T Cell Subsets ◽  
Activation Markers ◽  
Activated T Cell ◽  
Anti Inflammatory Cytokine

We recently reported a critical role for T cells in the induction of eosinophilic esophagitis (EE) in mice; however, the role of specific T cell subsets in disease pathogenesis is not yet understood. In the current study, we tested the hypothesis that allergen-induced EE develops in response to the disproportion of functionally different effector and regulatory T cells in the esophagus. Fluorescence-activated cell sorter analysis was performed to examine activated T cell subsets using the cell surface activation markers CD25 and CD69. A significant increase in activated CD4+ and CD4− T cells was observed in the total esophageal cells isolated from the mouse model of EE. Furthermore, an imbalance in the effector and regulatory T cells was observed in the esophagus. The esophageal CD4+CD45RBhigh effector T cells in allergen-challenged mice increased compared with saline-challenged mice (65.4 ± 3.6 × 103 to 44.8 ± 4.2 × 103), whereas CD4+CD45RBlow mostly regulatory T cells decreased in allergen-challenged mice compared with saline-challenged mice (5.8 ± 0.9 × 103 from 10.2 ± 1.7 × 103). The functional characteristics were examined by analysis of the pro- and anti-inflammatory cytokine profile of purified low and high CD4+CD45RB subsets from the spleen. Additionally, a significantly reduced interleukin (IL)-2 production by CD4+CD45RBlow cells in allergen-challenged mice compared with saline-challenged mice was observed. The reduced IL-2 in the CD4+CD45RBlow subset may be associated with reduction of CD4+CD45RBlow subset. In conclusion, our results suggest that local regulatory interaction of CD45RBhigh and CD45RBlow CD4+ T cells may be required for protective and pathogenic immunity in EE.

scholarly journals The role of peripheral T–cell deletion in transplantation tolerance

2001 ◽  
Vol 356 (1409) ◽  
pp. 617-623 ◽  
Author(s):  
Andrew D. Wells ◽  
Xian–Chang Li ◽  
Terry B. Strom ◽  
Laurence A. Turka
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Tolerance ◽  
Treatment Modalities ◽  
Transplantation Tolerance ◽  
Potential Contribution ◽  
Clonal Deletion ◽  
Self Tolerance ◽  
Clonal Anergy

The apoptotic deletion of thymocytes that express self–reactive antigen receptors is the basis of central (thymic) self–tolerance. However, it is clear that some autoreactive T cells escape deletion in the thymus and exist as mature lymphocytes in the periphery. Therefore, peripheral mechanisms of tolerance are also crucial, and failure of these peripheral mechanisms leads to autoimmunity. Clonal deletion, clonal anergy and immunoregulation and/or suppression have been suggested as mechanisms by which ‘inappropriate’ T–lymphocyte responses may be controlled in the periphery. Peripheral clonal deletion, which involves the apoptotic elimination of lymphocytes, is critical for T–cell homeostasis during normal immune responses, and is recognized as an important process by which self–tolerance is maintained. Transplantation of foreign tissue into an adult host represents a special case of ‘inappropriate’ T–cell reactivity that is subject to the same central and peripheral tolerance mechanisms that control reactivity against self. In this case, the unusually high frequency of naive T cells able to recognize and respond against non–self–allogeneic major histocompatibility complex (MHC) antigens leads to an exceptionally large pool of pathogenic effector lymphocytes that must be controlled if graft rejection is to be avoided. A great deal of effort has been directed toward understanding the role of clonal anergy and/or active immunoregulation in the induction of peripheral transplantation tolerance but, until recently, relatively little progress had been made towards defining the potential contribution of clonal deletion. Here, we outline recent data that define a clear requirement for deletion in the induction of peripheral transplantation tolerance across MHC barriers, and discuss the potential implications of these results in the context of current treatment modalities used in the clinical transplantation setting.

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.

The cannabinoid WIN55212‐2 suppresses effector T cell responses and promotes regulatory T cells in human tonsils

Allergy ◽  
2021 ◽  
Author(s):  
Alba Angelina ◽  
Mario Pérez‐Diego ◽  
Angel Maldonado ◽  
Beate Rückert ◽  
Mübeccel Akdis ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Responses ◽  
Effector T Cell ◽  
Cell Responses

Abstract 424: Effector T Cells Induce Cardiac Fibroblasts Transition to Myofibroblasts & Contribute to Pressure Overload Induced Cardiac Fibrosis

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Tania A Nevers ◽  
Ane Salvador ◽  
Francisco Velazquez ◽  
Mark Aronovitz ◽  
Robert Blanton
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Effector T Cells ◽  
T Cell Subsets ◽  
Naive T Cells ◽  
Effector T Cell ◽  
Naïve T Cells

Background: Cardiac fibrogenesis is a major pathogenic factor that occurs in heart failure (HF) and results in contractile dysfunction and ventricular dilation. Recently, we showed that T cell deficient mice (TCRα -/- ) do not develop cardiac fibrosis (CF) and have preserved cardiac function in the thoracic aortic constriction (TAC) mouse model of pressure overload (PO). Specifically, CD4 + T cells are activated in the cardiac draining lymph nodes and infiltrate the LV, where the Th1 and Th17 effector T cell signature transcription factors are significantly upregulated as compared with control mice. However, the T cell subsets involved and the mechanisms by which they contribute to CF and pathogenesis of non-ischemic HF remains to be determined. Thus, we hypothesize that heart infiltrated effector T cells perpetuate the fibrotic response by regulating the differentiation and activation of extracellular matrix-producing cardiac myofibroblasts. Methods and Results: Naïve or effector T cells differentiated in vitro or isolated from mice undergoing TAC or Sham surgery were co-cultured with adult C57BL/6 cardiac fibroblasts (CFB). In contrast with naïve T cells, effector T cells and PO activated T cells strongly adhered to CFB and mediated fibroblast to myofibroblasts transition as depicted by immunofluorescence expression of SMAα. Effector T cell supernatants only slightly mediated this transition, indicating that effector T cells direct contact with CFB, rather than cytokine release is required to mediate CFB transformation. Adoptive transfer of effector, but not naïve T cells, into TCRα -/- recipient mice in the onset of TAC resulted in T cells infiltration into the left ventricle and increased CF. Conclusions: Our data indicate that CD4+ effector T cells directly interact with CFB to induce CF in response to PO induced CF. Future studies will determine the adhesion mechanisms regulating this crosstalk and evaluate the pro-fibrotic mechanisms induced and whether this is a T effector cell specific subset. These results will provide an attractive tool to counteract the inflammatory/fibrotic process as an alternative option for the treatment of CF in non- ischemic HF.

scholarly journals Thymic Regulatory T Cell Development: Role of Signalling Pathways and Transcription Factors

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Mark Engel ◽  
Tom Sidwell ◽  
Ajithkumar Vasanthakumar ◽  
George Grigoriadis ◽  
Ashish Banerjee
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Tolerance ◽  
Regulatory T Cell ◽  
T Cell Development ◽  
Signalling Pathways ◽  
Treg Development

Regulatory T cells (Tregs) are a subset of CD4 T cells that are key mediators of immune tolerance. Most Tregs develop in the thymus. In this review we summarise recent findings on the role of diverse signalling pathways and downstream transcription factors in thymic Treg development.

scholarly journals Increased frequencies of CD4+CD25high regulatory T cells in acute dengue infection

2007 ◽  
Vol 204 (5) ◽  
pp. 979-985 ◽  
Author(s):  
Kerstin Lühn ◽  
Cameron P. Simmons ◽  
Edward Moran ◽  
Nguyen Thi Phuong Dung ◽  
Tran Nguyen Bich Chau ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Severe Disease ◽  
Acute Infection ◽  
Dengue Infection ◽  
Hemorrhagic Fever ◽  
Severe Dengue ◽  
Effector T Cell ◽  
Cell Effector

Dengue virus infection is an increasingly important tropical disease, causing 100 million cases each year. Symptoms range from mild febrile illness to severe hemorrhagic fever. The pathogenesis is incompletely understood, but immunopathology is thought to play a part, with antibody-dependent enhancement and massive immune activation of T cells and monocytes/macrophages leading to a disproportionate production of proinflammatory cytokines. We sought to investigate whether a defective population of regulatory T cells (T reg cells) could be contributing to immunopathology in severe dengue disease. CD4+CD25highFoxP3+ T reg cells of patients with acute dengue infection of different severities showed a conventional phenotype. Unexpectedly, their capacity to suppress T cell proliferation and to secrete interleukin-10 was not altered. Moreover, T reg cells suppressed the production of vasoactive cytokines after dengue-specific stimulation. Furthermore, T reg cell frequencies and also T reg cell/effector T cell ratios were increased in patients with acute infection. A strong indication that a relative rise of T reg cell/effector T cell ratios is beneficial for disease outcome comes from patients with mild disease in which this ratio is significantly increased (P < 0.0001) in contrast to severe cases (P = 0.2145). We conclude that although T reg cells expand and function normally in acute dengue infection, their relative frequencies are insufficient to control the immunopathology of severe disease.

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