scholarly journals Transforming Growth Factor-β CD4+T cells Tumor-bearing state Immunosuppression Enhanced Production of TGF-β and a Progressive Increase in TGF-β Susceptibility of Anti-tumor CD4+T Cell Function

1993 ◽  
Vol 84 (3) ◽  
pp. 315-325 ◽  
Author(s):  
Xiao-Fei Li ◽  
Hidekazu Takiuchi ◽  
Jian-Ping Zou ◽  
Tatsuo Katagiri ◽  
Norihiko Yamamoto ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Cell Function ◽  
Transforming Growth Factor Β ◽  
Progressive Increase ◽  
Cd4 T Cell ◽  
Tumor Bearing ◽  
Enhanced Production

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.

scholarly journals Piezo1 channels restrain regulatory T cells but are dispensable for effector CD4+ T cell responses

2021 ◽  
Vol 7 (28) ◽  
pp. eabg5859
Author(s):  
Amit Jairaman ◽  
Shivashankar Othy ◽  
Joseph L. Dynes ◽  
Andriy V. Yeromin ◽  
Angel Zavala ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Bacterial Infections ◽  
Transforming Growth Factor ◽  
Cell Function ◽  
Inflammatory Responses ◽  
Transforming Growth Factor Β ◽  
T Helper 1 ◽  
Cell Functions ◽  
Mechanosensitive Ion Channel

T lymphocytes encounter complex mechanical cues during an immune response. The mechanosensitive ion channel, Piezo1, drives inflammatory responses to bacterial infections, wound healing, and cancer; however, its role in helper T cell function remains unclear. In an animal model for multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), we found that mice with genetic deletion of Piezo1 in T cells showed diminished disease severity. Unexpectedly, Piezo1 was not essential for lymph node homing, interstitial motility, Ca2+ signaling, T cell proliferation, or differentiation into proinflammatory T helper 1 (TH1) and TH17 subsets. However, Piezo1 deletion in T cells resulted in enhanced transforming growth factor–β (TGFβ) signaling and an expanded pool of regulatory T (Treg) cells. Moreover, mice with deletion of Piezo1 specifically in Treg cells showed significant attenuation of EAE. Our results indicate that Piezo1 selectively restrains Treg cells, without influencing activation events or effector T cell functions.

scholarly journals Tumor-derived TGF-β inhibits mitochondrial respiration to suppress IFN-γ production by human CD4+ T cells

2019 ◽  
Vol 12 (599) ◽  
pp. eaav3334 ◽  
Author(s):  
Sarah Dimeloe ◽  
Patrick Gubser ◽  
Jordan Loeliger ◽  
Corina Frick ◽  
Leyla Develioglu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Atp Synthase ◽  
Transforming Growth Factor ◽  
Cell Function ◽  
Nuclear Translocation ◽  
Cell Metabolism ◽  
Transforming Growth Factor Β ◽  
Smad Proteins ◽  
Ifn Γ

Transforming growth factor–β (TGF-β) is produced by tumors, and increased amounts of this cytokine in the tumor microenvironment and serum are associated with poor patient survival. TGF-β–mediated suppression of antitumor T cell responses contributes to tumor growth and survival. However, TGF-β also has tumor-suppressive activity; thus, dissecting cell type–specific molecular effects may inform therapeutic strategies targeting this cytokine. Here, using human peripheral and tumor-associated lymphocytes, we investigated how tumor-derived TGF-β suppresses a key antitumor function of CD4+ T cells, interferon-γ (IFN-γ) production. Suppression required the expression and phosphorylation of Smad proteins in the TGF-β signaling pathway, but not their nuclear translocation, and depended on oxygen availability, suggesting a metabolic basis for these effects. Smad proteins were detected in the mitochondria of CD4+ T cells, where they were phosphorylated upon treatment with TGF-β. Phosphorylated Smad proteins were also detected in the mitochondria of isolated tumor-associated lymphocytes. TGF-β substantially impaired the ATP-coupled respiration of CD4+ T cells and specifically inhibited mitochondrial complex V (ATP synthase) activity. Last, inhibition of ATP synthase alone was sufficient to impair IFN-γ production by CD4+ T cells. These results, which have implications for human antitumor immunity, suggest that TGF-β targets T cell metabolism directly, thus diminishing T cell function through metabolic paralysis.

scholarly journals Role of Gastric Epithelial Cell-Derived Transforming Growth Factor β in Reduced CD4+T Cell Proliferation and Development of Regulatory T Cells during Helicobacter pylori Infection

2011 ◽  
Vol 79 (7) ◽  
pp. 2737-2745 ◽  
Author(s):  
Ellen J. Beswick ◽  
Iryna V. Pinchuk ◽  
Rachel B. Earley ◽  
David A. Schmitt ◽  
Victor E. Reyes
Keyword(s):  
T Cells ◽  
Helicobacter Pylori ◽  
T Cell ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
T Cell Responses ◽  
Transforming Growth Factor Β ◽  
Content Type ◽  
Cell Responses ◽  
H Pylori

ABSTRACTGastric epithelial cells (GECs) express the class II major histocompatibility complex (MHC) and costimulatory molecules, enabling them to act as antigen-presenting cells (APCs) and affect local T cell responses. DuringHelicobacter pyloriinfection, GECs respond by releasing proinflammatory cytokines and by increasing the surface expression of immunologically relevant receptors, including class II MHC. The CD4+T cell response duringH. pyloriinfection is skewed toward a Th1 response, but these cells remain hyporesponsive. Activated T cells show decreased proliferation duringH. pyloriinfection, and CD4+CD25+FoxP3+regulatory T cells (Tregs) are present at the site of infection. In this study, we examined the mechanisms surrounding the CD4+T cell responses duringH. pyloriinfection and found that transforming growth factor β (TGF-β) plays a major role in these responses. GECs produced TGF-β1 and TGF-β2 in response to infection. Activated CD4+T cells in culture withH. pylori-treated GECs were decreased in proliferation but increased upon neutralization of TGF-β. Naïve CD4+T cell development into Tregs was also enhanced in the presence of GEC-derived TGF-β. Herein, we demonstrate a role for GEC-produced TGF-β in the inhibition of CD4+T cell responses seen duringH. pyloriinfection.

scholarly journals Transforming growth factor-β signaling is constantly shaping memory T-cell population

2015 ◽  
Vol 112 (35) ◽  
pp. 11013-11017 ◽  
Author(s):  
Chaoyu Ma ◽  
Nu Zhang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Growth Factor ◽  
Cell Population ◽  
Transforming Growth Factor ◽  
Memory T Cells ◽  
Transforming Growth Factor Β ◽  
Memory T Cell

The long-term maintenance of memory T cells is essential for successful vaccines. Both the quantity and the quality of the memory T-cell population must be maintained. The signals that control the maintenance of memory T cells remain incompletely identified. Here we used two genetic models to show that continuous transforming growth factor-β signaling to antigen-specific T cells is required for the differentiation and maintenance of memory CD8+ T cells. In addition, both infection-induced and microbiota-induced inflammation impact the phenotypic and functional identity of memory CD8+ T cells.

scholarly journals Low-strength T-cell activation promotes Th17 responses

Blood ◽  
2010 ◽  
Vol 116 (23) ◽  
pp. 4829-4837 ◽  
Author(s):  
Harriet A. Purvis ◽  
Jeroen N. Stoop ◽  
Jelena Mann ◽  
Steven Woods ◽  
Anne E. Kozijn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Growth Factor ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 17

Abstract We show that the strength of T-cell stimulation determines the capability of human CD4+ T cells to become interleukin-17 (IL-17) producers. CD4+ T cells received either high- (THi) or low (TLo)–strength stimulation via anti-CD3/CD28 beads or dendritic cells pulsed with superantigen in the presence of pro-Th17 cytokines IL-1β, transforming growth factor β, and IL-23. We found that TLo, but not THi, stimulation profoundly promoted Th17 responses by enhancing both the relative proportion and total number of Th17 cells. Titration of anti-CD3 revealed that low TCR signaling promoted Th17 cells, but only in the presence of anti-CD28. Impaired IL-17 production in THi cells could not be explained by high levels of Foxp3 or transforming growth factor β–latency-associated peptide expressed by THi cells. Nuclear factor of activated T cells was translocated to the nucleus in both THi and TLo cells, but only bound to the proximal region of the IL-17 promoter in TLo cells. The addition of a Ca2+ ionophore under TLo conditions reversed the pro-Th17 effect, suggesting that high Ca2+ signaling impairs Th17 development. Although our data do not distinguish between priming of naive T cells versus expansion/differentiation of memory T cells, our results clearly establish an important role for the strength of T-cell activation in regulating Th17 responses.

scholarly journals Induction of FOXP3 expression in naive human CD4+FOXP3− T cells by T-cell receptor stimulation is transforming growth factor-β–dependent but does not confer a regulatory phenotype

Blood ◽  
2007 ◽  
Vol 110 (8) ◽  
pp. 2983-2990 ◽  
Author(s):  
Dat Q. Tran ◽  
Heather Ramsey ◽  
Ethan M. Shevach
Keyword(s):  
T Cells ◽  
T Cell ◽  
Growth Factor ◽  
T Cell Receptor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Foxp3 Expression ◽  
Cell Receptor ◽  
T Regulatory Cell ◽  
Regulatory Phenotype

Abstract Thymic-derived natural T-regulatory cells (nTregs) are important for the induction of self-tolerance and the control of autoimmunity. Murine CD4+CD25−Foxp3− cells can be induced to express Foxp3 after T-cell receptor (TCR) activation in the presence of transforming growth factor β (TGFβ) and are phenotypically similar to nTregs. Some studies have suggested that TCR stimulation of human CD4+CD25− cells results in the induction of transient expression of FOXP3, but that the induced cells lack a regulatory phenotype. We demonstrate here that TCR stimulation alone was insufficient to induce FOXP3 expression in the absence of TGFβ, whereas high levels of FOXP3 expression could be induced in the presence of TGFβ. Although FOXP3 expression was stable, the TGFβ-induced FOXP3+ T cells were neither anergic nor suppressive and produced high levels of effector cytokines. These results suggest that even high levels of FOXP3 expression are insufficient to define a human CD4+ T cell as a T-regulatory cell.

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