Interaction between B7-H1 and PD-1 determines initiation and reversal of T-cell anergy

Although self-reactive T-cell precursors can be eliminated upon recognition of self-antigen presented in the thymus, this central tolerance process is often incomplete, and additional mechanisms are required to prevent autoimmunity. Recent studies indicates that the interaction between B7-H1 and its receptor PD-1 on activated T cells plays an important role in the inhibition of T-cell responses in peripheral organs. Here, we show that, before their exit to the periphery, T cells in lymphoid organs rapidly up-regulate PD-1 upon tolerogen recognition. Ablation of the B7-H1 and PD-1 interaction when T cells are still in lymphoid organs prevents anergy. Furthermore, blockade of B7-H1 and PD-1 interaction could render anergic T cells responsive to antigen. Our results thus reveal previously unappreciated roles of B7-H1 and PD-1 interaction in the control of initiation and reversion of T-cell anergy.

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Induction of CD4+ T-cell anergy and apoptosis by activated human B cells

Blood ◽

10.1182/blood-2008-02-140087 ◽

2008 ◽

Vol 112 (12) ◽

pp. 4555-4564 ◽

Cited By ~ 55

Author(s):

Theresa Tretter ◽

Ram K. C. Venigalla ◽

Volker Eckstein ◽

Rainer Saffrich ◽

Serkan Sertel ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Cell Contact ◽

Activated T Cells ◽

Cell Responses ◽

T Cell Anergy ◽

Human B Cells ◽

Cell Anergy

Abstract B cells are well-known mediators of humoral immunity and serve as costimulators in the generation of T cell–mediated responses. In several mouse models, however, it was observed that B cells can also down-regulate immune reactions, suggesting a dual role for B cells. Due to this discrepancy and so far limited data, we directly tested the effects of primary human B cells on activated CD4+ T helper cells in vitro. We found that under optimal costimulation large, activated CD25+ B cells but not small CD25− B cells induced temporary T-cell anergy, determined by cell division arrest and down-regulation of cytokine production. In addition, large CD25+ B cells directly induced CD95-independent apoptosis in a subpopulation of activated T cells. Suppression required direct B-T-cell contact and was not transferable from T to T cell, excluding potential involvement of regulatory T cells. Moreover, inhibitory effects involved an IL-2–dependent mechanism, since decreasing concentrations of IL-2 led to a shift from inhibitory toward costimulatory effects triggered by B cells. We conclude that activated CD25+ B cells are able to costimulate or down-regulate T-cell responses, depending on activation status and environmental conditions that might also influence their pathophysiological impact.

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Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells.

Journal of Experimental Medicine ◽

10.1084/jem.184.1.19 ◽

1996 ◽

Vol 184 (1) ◽

pp. 19-29 ◽

Cited By ~ 549

Author(s):

H Groux ◽

M Bigler ◽

J E de Vries ◽

M G Roncarolo

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Interleukin 10 ◽

Necrosis Factor Alpha ◽

T Cell Anergy ◽

Factor Alpha ◽

Cell Anergy ◽

Anergic T Cells ◽

Macrophage Colony

Human CD4+ T cells, activated by allogeneic monocytes in a primary mixed lymphocyte reaction in the presence of exogenous interleukin (IL) 10, specifically failed to proliferate after restimulation with the same alloantigens. A comparable state of T cell unresponsiveness could be induced by activation of CD4+ T cells by cross-linked anti-CD3 monoclonal antibodies (mAbs) in the presence of exogenous IL-10. The anergic T cells failed to produce IL-2, IL-5, IL-10, interferon gamma, tumor necrosis factor alpha, and granulocyte/macrophage colony-stimulating factor. The IL-10-induced anergic state was long-lasting. T cell anergy could not be reversed after restimulation of the cells with anti-CD3 and anti-CD28 mAbs, although CD3 and CD28 expression was normal. In addition, restimulation of anergized T cells with anti-CD3 mAbs induced normal Ca2+ fluxes and resulted in increased CD3, CD28, and class II major histocompatibility complex expression, indicating that calcineurin-mediated signaling occurs in these anergic cells. However, the expression of the IL-2 receptor alpha chain was not upregulated, which may account for the failure of exogenous IL-2 to reverse the anergic state. Interestingly, anergic T cells and their nonanergic counterparts showed comparable levels of proliferation and cytokine production after activation with phorbol myristate acetate and Ca2+ ionophore, indicating that a direct activation of a protein kinase C-dependent pathway can overcome the tolerizing effect of IL-10. Taken together, these data demonstrate that IL-10 induces T cell anergy and therefore may play an important role in the induction and maintenance of antigen-specific T cell tolerance.

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PAG-Associated FynT Regulates Calcium Signaling and Promotes Anergy in T Lymphocytes

Molecular and Cellular Biology ◽

10.1128/mcb.01983-06 ◽

2007 ◽

Vol 27 (5) ◽

pp. 1960-1973 ◽

Cited By ~ 50

Author(s):

Dominique Davidson ◽

Burkhart Schraven ◽

André Veillette

Keyword(s):

T Cells ◽

T Cell ◽

Tyrosine Phosphorylation ◽

T Cell Activation ◽

Protein Tyrosine Kinase ◽

Cell Activation ◽

T Cell Anergy ◽

Cell Anergy ◽

Anergic T Cells ◽

Selective Enhancement

ABSTRACT Phosphoprotein associated with glycolipid-enriched membranes (PAG), also named Csk-binding protein (Cbp), is a transmembrane adaptor associated with lipid rafts. It is phosphorylated on multiple tyrosines located in the cytoplasmic domain. One tyrosine, tyrosine 314 (Y314) in the mouse, interacts with Csk, a protein tyrosine kinase that negatively regulates Src kinases. This interaction enables PAG to inhibit T-cell antigen receptor (TCR)-mediated T-cell activation. PAG also associates with the Src-related kinase FynT. Genetic studies indicated that FynT was required for PAG tyrosine phosphorylation and binding of PAG to Csk in T cells. Herein, we investigated the function and regulation of PAG-associated FynT. Our data showed that PAG was constitutively associated with FynT in unstimulated T cells and that this association was rapidly lost in response to TCR stimulation. Dissociation of the PAG-FynT complex preceded PAG dephosphorylation and PAG-Csk dissociation after TCR engagement. Interestingly, in anergic T cells, the association of PAG with FynT, but not Csk, was increased. Analyses of PAG mutants provided evidence that PAG interacted with FynT by way of tyrosines other than Y314. Enforced expression of a PAG variant interacting with FynT, but not Csk, caused a selective enhancement of TCR-triggered calcium fluxes in normal T cells. Furthermore, it promoted T-cell anergy. Both effects were absent in mice lacking FynT, implying that the effects were mediated by PAG-associated FynT. Hence, besides enabling PAG tyrosine phosphorylation and the PAG-Csk interaction, PAG-associated FynT can stimulate calcium signals and favor T-cell anergy. These data improve our comprehension of the function of PAG in T cells. They also further implicate FynT in T-cell anergy.

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Cbl-b deficiency prevents functional but not phenotypic T cell anergy

Journal of Experimental Medicine ◽

10.1084/jem.20202477 ◽

2021 ◽

Vol 218 (7) ◽

Author(s):

Trang T.T. Nguyen ◽

Zhi-En Wang ◽

Lin Shen ◽

Andrew Schroeder ◽

Walter Eckalbar ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Peripheral Tolerance ◽

Tolerance Mechanism ◽

Tcr Signaling ◽

Mhc Ii ◽

T Cell Anergy ◽

Cell Anergy ◽

Anergic T Cells ◽

Tolerance Gene

T cell anergy is an important peripheral tolerance mechanism. We studied how T cell anergy is established using an anergy model in which the Zap70 hypermorphic mutant W131A is coexpressed with the OTII TCR transgene (W131AOTII). Anergy was established in the periphery, not in the thymus. Contrary to enriched tolerance gene signatures and impaired TCR signaling in mature peripheral CD4 T cells, CD4SP thymocytes exhibited normal TCR signaling in W131AOTII mice. Importantly, the maintenance of T cell anergy in W131AOTII mice required antigen presentation via MHC-II. We investigated the functional importance of the inhibitory receptor PD-1 and the E3 ubiquitin ligases Cbl-b and Grail in this model. Deletion of each did not affect expression of phenotypic markers of anergic T cells or T reg numbers. However, deletion of Cbl-b, but not Grail or PD-1, in W131AOTII mice restored T cell responsiveness and signaling. Thus, Cbl-b plays an essential role in the establishment and/or maintenance of unresponsiveness in T cell anergy.

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T–cell anergy and peripheral T–cell tolerance

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2001.0844 ◽

2001 ◽

Vol 356 (1409) ◽

pp. 625-637 ◽

Cited By ~ 23

Author(s):

Robert Lechler ◽

Jian-Guo Chai ◽

Federica Marelli-Berg ◽

Giovanna Lombardi

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Contact ◽

T Cell Tolerance ◽

Cell Tolerance ◽

T Cell Anergy ◽

Cell Anergy ◽

Anergic T Cells

The discovery that T–cell recognition of antigen can have distinct outcomes has advanced understanding of peripheral T–cell tolerance, and opened up new possibilities in immunotherapy. Anergy is one such outcome, and results from partial T–cell activation. This can arise either due to subtle alteration of the antigen, leading to a lower–affinity cognate interaction, or due to a lack of adequate co–stimulation. The signalling defects in anergic T cells are partially defined, and suggest that T–cell receptor (TCR) proximal, as well as downstream defects negatively regulate the anergic T cell's ability to be activated. Most importantly, the use of TCR–transgenic mice has provided compelling evidence that anergy is an in vivo phenomenon, and not merely an in vitro artefact. These findings raise the question as to whether anergic T cells have any biological function. Studies in rodents and in man suggest that anergic T cells acquire regulatory properties; the regulatory effects of anergic T cells require cell to cell contact, and appear to be mediated by inhibition of antigen–presenting cell immunogenicity. Close similarities exist between anergic T cells, and the recently defined CD4 + CD25 + population of spontaneously arising regulatory cells that serve to inhibit autoimmunity in mice. Taken together, these findings suggest that a spectrum of regulatory T cells exists. At one end of the spectrum are cells, such as anergic and CD4 + CD25 + T cells, which regulate via cell–to–cell contact. At the other end of the spectrum are cells which secrete antiinflammatory cytokines such as interleukin 10 and transforming growth factor–β. The challenge is to devise strategies that reliably induce T–cell anergy in vivo , as a means of inhibiting immunity to allo– and autoantigens.

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144 T cell anergy regulator Egr2 identifies a quiescent stem-like phenotype in malignant T cells

Journal of Investigative Dermatology ◽

10.1016/j.jid.2017.02.158 ◽

2017 ◽

Vol 137 (5) ◽

pp. S24

Author(s):

H. Hamidullah ◽

S. Roy ◽

A. Anshu ◽

W. Kittipongdaja ◽

S.M. Schieke

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Anergy ◽

Cell Anergy ◽

Malignant T Cells

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Modulation of let-7 miRNAs controls the differentiation of effector CD8 T cells

eLife ◽

10.7554/elife.26398 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 31

Author(s):

Alexandria C Wells ◽

Keith A Daniels ◽

Constance C Angelou ◽

Eric Fagerberg ◽

Amy S Burnside ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Lymphocytes ◽

Cytotoxic T Lymphocytes ◽

Cd8 T Cells ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Receptor ◽

Activated T Cells ◽

Cell Responses

The differentiation of naive CD8 T cells into effector cytotoxic T lymphocytes upon antigen stimulation is necessary for successful antiviral, and antitumor immune responses. Here, using a mouse model, we describe a dual role for the let-7 microRNAs in the regulation of CD8 T cell responses, where maintenance of the naive phenotype in CD8 T cells requires high levels of let-7 expression, while generation of cytotoxic T lymphocytes depends upon T cell receptor-mediated let-7 downregulation. Decrease of let-7 expression in activated T cells enhances clonal expansion and the acquisition of effector function through derepression of the let-7 targets, including Myc and Eomesodermin. Ultimately, we have identified a novel let-7-mediated mechanism, which acts as a molecular brake controlling the magnitude of CD8 T cell responses.

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