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.

Altered T-cell receptor + CD28-mediated signaling and blocked cell cycle progression in interleukin 10 and transforming growth factor-β–treated alloreactive T cells that do not induce graft-versus-host disease

Blood ◽  
2001 ◽  
Vol 97 (2) ◽  
pp. 565-571 ◽  
Author(s):  
Vassiliki A. Boussiotis ◽  
Zong-Ming Chen ◽  
Jay C. Zeller ◽  
William J. Murphy ◽  
Alla Berezovskaya ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Receptor ◽  
Interleukin 10 ◽  
Graft Versus Host

Abstract The induction of anergy in T cells, although widely accepted as critical for the maintenance of tolerance, is still poorly understood at the molecular level. Recent evidence demonstrates that in addition to blockade of costimulation using monoclonal antibodies (mAbs) directed against cell surface determinants, treatment of mixed lymphocyte reaction (MLR) cultures with interleukin 10 (IL-10) and transforming growth factor-β (TGF-β) results in induction of tolerance, rendering alloreactive murine CD4+ T cells incapable of inducing graft-versus-host disease (GVHD) after in vivo transfer to histoincompatible recipients. The present study, using these cells prior to adoptive transfer, determined that IL-10 + TGF-β–tolerant CD4+ T cells exhibit an altered pattern of T-cell receptor (TCR) + CD28-mediated signaling and are incapable of progressing out of the G1 phase of the cell cycle during stimulation with HLA class II disparate antigen-presenting cells. TGFβ + IL-10–tolerant cells were incapable of phosphorylating TCR-ζ, or activating ZAP-70, Ras, and MAPK, similarly to T-cell tolerized by blockade of B7/CD28 and CD40/CD40L pathways. Moreover, these cells were incapable of clonal expansion due to defective synthesis of cyclin D3 and cyclin A, and defective activation of cyclin-dependent kinase (cdk)4, cdk6, and cdk2. These cells also exhibited defective down-regulation of p27kip1 cdk inhibitor and lack of cyclin D2-cdk4 activation, Rb hyperphosphorylation, and progression to the S phase of the cell cycle. These data link anergy-specific proximal biochemical alterations and the downstream nuclear pathways that control T-cell expansion and provide a biochemical profile of IL-10 + TGF-β–tolerant alloreactive T cells that do not induce GVHD when transferred into MHC class II disparate recipients in vivo.

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.

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