scholarly journals CD8+ Regulatory T Cell – A Mystery to Be Revealed

2021 ◽  
Vol 12 ◽  
Author(s):  
Shruti Mishra ◽  
Saranya Srinivasan ◽  
Chaoyu Ma ◽  
Nu Zhang
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Regulatory T Cells ◽  
Regulatory T Cell ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
T Cell Subsets ◽  
Molecular Regulation ◽  
Open Questions

Regulatory T cells (Treg) are essential to maintain immune homeostasis and prevent autoimmune disorders. While the function and molecular regulation of Foxp3+CD4+ Tregs are well established, much of CD8+ Treg biology remains to be revealed. Here, we will review the heterogenous subsets of CD8+ T cells have been named “CD8+ Treg” and mainly focus on CD122hiLy49+CD8+ Tregs present in naïve mice. CD122hiLy49+CD8+ Tregs, which depends on transcription factor Helios and homeostatic cytokine IL-15, have been established as a non-redundant regulator of germinal center (GC) reaction. Recently, we have demonstrated that TGF-β (Transforming growth factor-β) and transcription factor Eomes (Eomesodermin) are essential for the function and homeostasis of CD8+ Tregs. In addition, we will discuss several open questions regarding the differentiation, function and true identity of CD8+ Tregs as well as a brief comparison between two regulatory T cell subsets critical to control GC reaction, namely CD4+ TFR (follicular regulatory T cells) and CD8+ Tregs.

scholarly journals Regulation of Human CD4+ αβ T-Cell-Receptor-Positive (TCR+) and γδ TCR+ T-Cell Responses to Mycobacterium tuberculosis by Interleukin-10 and Transforming Growth Factor β

1999 ◽  
Vol 67 (12) ◽  
pp. 6461-6472 ◽  
Author(s):  
Roxana E. Rojas ◽  
Kithiganahalli N. Balaji ◽  
Ahila Subramanian ◽  
W. Henry Boom
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Γδ T Cells ◽  
T Cell Responses ◽  
Transforming Growth Factor Β ◽  
T Cell Subsets ◽  
Cell Responses

ABSTRACT Mycobacterium tuberculosis is the etiologic agent of human tuberculosis and is estimated to infect one-third of the world's population. Control of M. tuberculosis requires T cells and macrophages. T-cell function is modulated by the cytokine environment, which in mycobacterial infection is a balance of proinflammatory (interleukin-1 [IL-1], IL-6, IL-8, IL-12, and tumor necrosis factor alpha) and inhibitory (IL-10 and transforming growth factor β [TGF-β]) cytokines. IL-10 and TGF-β are produced by M. tuberculosis-infected macrophages. The effect of IL-10 and TGF-β on M. tuberculosis-reactive human CD4+and γδ T cells, the two major human T-cell subsets activated byM. tuberculosis, was investigated. Both IL-10 and TGF-β inhibited proliferation and gamma interferon production by CD4+ and γδ T cells. IL-10 was a more potent inhibitor than TGF-β for both T-cell subsets. Combinations of IL-10 and TGF-β did not result in additive or synergistic inhibition. IL-10 inhibited γδ and CD4+ T cells directly and inhibited monocyte antigen-presenting cell (APC) function for CD4+ T cells and, to a lesser extent, for γδ T cells. TGF-β inhibited both CD4+ and γδ T cells directly and had little effect on APC function for γδ and CD4+ T cells. IL-10 down-regulated major histocompatibility complex (MHC) class I, MHC class II, CD40, B7-1, and B7-2 expression on M. tuberculosis-infected monocytes to a greater extent than TGF-β. Neither cytokine affected the uptake of M. tuberculosis by monocytes. Thus, IL-10 and TGF-β both inhibited CD4+ and γδ T cells but differed in the mechanism used to inhibit T-cell responses to M. tuberculosis.

Human immunodeficiency virus–driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients

Blood ◽  
2004 ◽  
Vol 104 (10) ◽  
pp. 3249-3256 ◽  
Author(s):  
Laurence Weiss ◽  
Vladimira Donkova-Petrini ◽  
Laure Caccavelli ◽  
Michèle Balbo ◽  
Cédric Carbonneil ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Highly Active Antiretroviral Therapy ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Cell Subset ◽  
Transforming Growth Factor Β ◽  
Interleukin 10

Abstract The present study demonstrates that CD4+CD25+ T cells, expanded in peripheral blood of HIV-infected patients receiving highly active antiretroviral therapy (HAART), exhibit phenotypic, molecular, and functional characteristics of regulatory T cells. The majority of peripheral CD4+CD25+ T cells from HIV-infected patients expressed a memory phenotype. They were found to constitutively express transcription factor forkhead box P3 (Foxp3) messengers. CD4+CD25+ T cells weakly proliferated to immobilized anti-CD3 monoclonal antibody (mAb) and addition of soluble anti-CD28 mAb significantly increased proliferation. In contrast to CD4+CD25– T cells, CD4+CD25+ T cells from HIV-infected patients did not proliferate in response to recall antigens and to p24 protein. The proliferative capacity of CD4 T cells to tuberculin, cytomegalovirus (CMV), and p24 significantly increased following depletion of CD4+CD25+ T cells. Furthermore, addition of increasing numbers of CD4+CD25+ T cells resulted in a dose-dependent inhibition of CD4+CD25– T-cell proliferation to tuberculin and p24. CD4+CD25+ T cells responded specifically to p24 antigen stimulation by expressing transforming growth factor β (TGF-β) and interleukin 10 (IL-10), thus indicating the presence of p24-specific CD4+ T cells among the CD4+CD25+ T-cell subset. Suppressive activity was not dependent on the secretion of TGF-β or IL-10. Taken together, our results suggest that persistence of HIV antigens might trigger the expansion of CD4+CD25+ regulatory T cells, which might induce a tolerance to HIV in vivo.

Absence of clinical GVHD and the in vivo induction of regulatory T cells after transplantation of facilitating cells

Blood ◽  
2004 ◽  
Vol 104 (12) ◽  
pp. 3829-3835 ◽  
Author(s):  
Yolonda L. Colson ◽  
Kenneth Christopher ◽  
Jonathan Glickman ◽  
Kendra N. Taylor ◽  
Renee Wright ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cell ◽  
Transforming Growth Factor ◽  
Cell Model ◽  
Transforming Growth Factor Β ◽  
Hematopoietic Stem ◽  
Novel Approach ◽  
Cell Induction

Graft-versus-host disease (GVHD) and failure of engraftment limit clinical bone marrow transplantation (BMT) to patients with closely matched donors. Engraftment failure of purified allogeneic hematopoietic stem cells (HSCs) has been decreased in various BMT models by including donor BM–derived CD8+/αβγδTCR- facilitating cells (FCs) or CD8+/αβTCR+ T cells in the BM inoculum. To aggressively investigate the GVHD potential of these donor CD8+ populations, a purified cell model of lethal GVHD was established in a murine semiallogeneic parent → F1 combination. Lethally irradiated recipients were reconstituted with purified donor HSCs alone or in combination with splenic T cells (TSP), BM-derived T cells (TBM), or the FC population. In marked contrast to the lethal GVHD present in recipients of HSCs plus TSP or CD8+ TBM, recipients of donor HSC+FC inocula did not exhibit significant clinical or histologic evidence of GVHD. Instead, HSC+FC recipients were characterized by increased splenocyte expression of transforming growth factor-β (TGF-β) and the induction of the regulatory T-cell genes CTLA4, GITR, and FoxP3. These findings suggest that the FCs, which express a unique FCp33-TCRβ heterodimer in place of αβTCR, permits HSC alloengraftment and prevents GVHD through the novel approach of regulatory T-cell induction in vivo.

scholarly journals Identification of an immediate Foxp3− precursor to Foxp3+ regulatory T cells in peripheral lymphoid organs of nonmanipulated mice

2010 ◽  
Vol 207 (7) ◽  
pp. 1393-1407 ◽  
Author(s):  
Sonja Schallenberg ◽  
Pei-Yun Tsai ◽  
Julia Riewaldt ◽  
Karsten Kretschmer
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Transforming Growth Factor ◽  
Interleukin 2 ◽  
Transforming Growth Factor Β ◽  
Cell Receptor ◽  
Lymphoid Organs ◽  
Minor Role ◽  
A Minor

CD4+CD25+ regulatory T cells (T reg cells) expressing the transcription factor Foxp3 can be induced from peripheral T cell receptor (TCR) transgenic CD4+CD25−Foxp3− T cells stimulated with noninflammatory dendritic cells presenting low amounts of agonist cognate antigen. However, limited evidence exists for extra-thymic T reg cell generation from non-TCR transgenic T cells in unmanipulated mice. We compared events early during agonist-driven generation of Foxp3+ TCR transgenic T cells to polyclonal CD4+ T cell populations in unmanipulated mice. We identified an interleukin-2– and phosphatidylinositol-3-kinase–dependent precommitted Foxp3− precursor to Foxp3+ T reg cells in peripheral lymphoid organs. Transforming growth factor β signaling played a minor role in the generation and subsequent differentiation of these T reg precursor cells.

scholarly journals Platelet-Derived GARP Induces Peripheral Regulatory T Cells—Potential Impact on T Cell Suppression in Patients with Melanoma-Associated Thrombocytosis

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3653
Author(s):  
Niklas Zimmer ◽  
Franziska K. Krebs ◽  
Sophia Zimmer ◽  
Heidrun Mitzel-Rink ◽  
Elena J. Kumm ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Interaction ◽  
Platelet Surface ◽  
T Effector Cells

Platelets have been recently described as an important component of the innate and adaptive immunity through their interaction with immune cells. However, information on the platelet–T cell interaction in immune-mediated diseases remains limited. Glycoprotein A repetitions predominant (GARP) expressed on platelets and on activated regulatory T cells (Treg) is involved in the regulation of peripheral immune responses by modulating the bioavailability of transforming growth factor β (TGF-β). Soluble GARP (sGARP) exhibits strong regulatory and anti-inflammatory capacities both in vitro and in vivo, leading to the induction of peripheral Treg. Herein, we investigated the effect of platelet-derived GARP on the differentiation, phenotype, and function of T effector cells. CD4+CD25− T cells cocultured with platelets upregulated FoxP3, the master transcription factor for Treg, were anergic, and were strongly suppressive. These effects were reversed by using a blocking anti-GARP antibody, indicating a dependency on GARP. Importantly, melanoma patients in different stages of disease showed a significant upregulation of GARP on the platelet surface, correlating to a reduced responsiveness to immunotherapy. In conclusion, our data indicate that platelets induce peripheral Treg via GARP. These findings might contribute to diseases such as cancer-associated thrombocytosis, wherein poor prognosis and metastasis are associated with high counts of circulating platelets.

Increased Regulatory T Cell Subsets (TReg and Tr1 Cells) in the Peripheral Blood of Patients with Multiple Myeloma Correlate with Disease Stage.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5070-5070
Author(s):  
Sylvia Feyler ◽  
Lee Marles ◽  
Stevie Richards ◽  
Gordon Cook
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Population ◽  
Regulatory T Cell ◽  
Peripheral Blood ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Control Group ◽  
Refractory Disease

Abstract The immunologically hostile microenviroment of multiple Myeloma may contribute to the limited success of immunotherapy strategies. In addition to direct tumour-induced immunosuppression, tumour cells may generate suppressor cells to further suppress the immune effectors. Regulatory T-cells profoundly suppress immune responses and induce tolerance and 2 main subsets have been identified: Naturally Occurring TReg cells and Inducible regulatory Tr-1 cells. The association between tumour cells and regulatory T cells has not been studied in haematological malignancies, especially those of B lymphocyte lineages. Therefore, this the aim of this study is to determine if regulatory T-cell subsets are increased in the peripheral blood of patients with MM and how this varies with increasing disease burden. Peripheral blood from patients with MM (De novo, n=3; Low Disease burden, n=19; Relapsed/Refractory Disease, n=11) and MGUS (n=6) with a median age of 69 years old (range 39–89 yrs) were analysed by flow cytometry and compared to age-sex matched controls (n=20, median age 60 yrs, range 33–80 yrs). Whilst there was no significant difference in the absolute lymphocyte counts between MM patients and controls (1.58x109/l ±0.14 vs. 1.9x109/l ±0.1, p=0.05) a significant CD4+ T-cell lymphopenia was noted in patients with MM compared to controls (393±62 cells/μl vs. 849±95 cells/μl, p<0.001). The CD4+ T-cell lymphopenia was most marked in patients with relapsed/refractory disease (462±114 cells/μl) and low tumour burden (380±85 cells/μl) compared with newly diagnosed patients (875±64 cells/μl, p<0.001), MGUS (945±90 cells/μl, p<0.001) and controls (849±95 cells/μl, p<0.001). Using a sequential gating strategy, TReg cells were identified as CD4±/CD25+/GITR+ T-cells and expressed as a percentage of the CD4+T-cell population. Overall, patients with MM demonstrated a significant increase in the TReg cell population compared to the control group (15.0%±2.5 vs. 7.2%±1.1, p<0.001). The increased TReg cell population was most marked in patients with relapsed/refractory disease (13.6%±1.5) and low tumour burden (16%±1.9) compared with newly diagnosed patients (6.7%±1.0, p<0.001), MGUS (10.8%±1.7, p=0.03) and controls (7.2%±1.1, p<0.001). Tr1 cells were analysed using an in-house assay and identified on a sequential gating strategy as CD4+/IL-10+/IL-4− T-cells and expressed as a percentage of the CD4+T-cell population. Overall, patients with MM demonstrated an increase in the Tr1 cell population compared to the control group (14.5%±5.5 vs. 9.8%±1.0) though the trend did not reach statistical significance (p=0.23). Similarly, an alteration in the Th1/Th2 balance was seen with an increase in the Th2 cell population compared to the control group (6.3%±3 vs. 2.8%±0.1) though the trend did not reach statistical significance (p=0.15). These results provide further evidence of immune dysregulation in patients with MM and suggest that tumour-associated immunosuppression may be mediated through the actions of regulatory T-cell subsets. In particular, the association with advanced disease stage suggests a casual association between the malignant cells and induction of immune regulatory cells. Further work in establishing a casual association between MM tumour cells and regulatory T-cells is on-going and is essential if immunotherapeutic strategies are ever to reach their full potential.

Anti-CD20 therapy corrects a CD8 regulatory T cell deficit in multiple sclerosis

2021 ◽  
pp. 135245852110033
Author(s):  
Quentin Howlett-Prieto ◽  
Xuan Feng ◽  
John F Kramer ◽  
Kevin J Kramer ◽  
Timothy W Houston ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
B Cell ◽  
Regulatory T Cell ◽  
Healthy Controls ◽  
Regulatory Cells ◽  
Long Term Treatment ◽  
Anti Cd20

Objective: To determine the effect of long-term anti-CD20 B-cell-depleting treatment on regulatory T cell immune subsets that are subnormal in untreated MS patients. Methods: 30 clinically stable MS patients, before and over 38 months of ocrelizumab treatment, were compared to 13 healthy controls, 29 therapy-naïve MS, 9 interferon-β-treated MS, 3 rituximab-treated MS, and 3 rituximab-treated patients with other autoimmune inflammatory diseases. CD8, CD28, CD4, and FOXP3 expression in peripheral blood mononuclear cells was quantitated with flow cytometry. Results: CD8+ CD28− regulatory cells rose from one-third of healthy control levels before ocrelizumab treatment (2.68% vs 7.98%), normalized by 12 months (13.5%), and rose to 2.4-fold above healthy controls after 18 months of ocrelizumab therapy (19.0%). CD4+ FOXP3+ regulatory cells were lower in MS than in healthy controls (7.98%) and showed slight long-term decreases with ocrelizumab. CD8+ CD28− and CD4+ FOXP3+ regulatory T cell percentages in IFN-β-treated MS patients were between those of untreated MS and healthy controls. Interpretation: Long-term treatment with ocrelizumab markedly enriches CD8+ CD28− regulatory T cells and corrects the low levels seen in MS before treatment, while slightly decreasing CD4+ FOXP3+ regulatory T cells. Homeostatic enrichment of regulatory CD8 T cells provides a mechanism, in addition to B cell depletion, for the benefits of anti-CD20 treatment in MS.

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