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

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.

Download Full-text

T1212 Upregulation of E3 Ubiquitin Ligases Related to T Cell Anergy in CD4+ T Cells Isolated from Patients with Ulcerative Colitis in Remission

Gastroenterology ◽

10.1016/s0016-5085(08)62369-0 ◽

2008 ◽

Vol 134 (4) ◽

pp. A-508

Author(s):

Satoshi Egawa ◽

Hideki Iijima ◽

Shinichiro Shinzaki ◽

Sachiko Nakajima ◽

Jumpei Kondo ◽

...

Keyword(s):

Ulcerative Colitis ◽

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Ubiquitin Ligases ◽

E3 Ubiquitin Ligases ◽

T Cell Anergy ◽

Cell Anergy

Download Full-text

1L-10 induces antigen-specific T-cell anergy but no regulatory T cells in children with Egg allergy

Journal of Allergy and Clinical Immunology ◽

10.1016/s0091-6749(03)80309-3 ◽

2003 ◽

Vol 111 (2) ◽

pp. S106-S107

Author(s):

P.A. Eigenmann ◽

L. Tropia ◽

C. Hauser ◽

C.P. Frossard

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Egg Allergy ◽

T Cell Anergy ◽

Cell Anergy

Download Full-text

T cell anergy in perinatal mice is promoted by T reg cells and prevented by IL-33

Journal of Experimental Medicine ◽

10.1084/jem.20182002 ◽

2019 ◽

Vol 216 (6) ◽

pp. 1328-1344 ◽

Cited By ~ 8

Author(s):

Jonatan Tuncel ◽

Christophe Benoist ◽

Diane Mathis

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

High Expression ◽

T Cell Anergy ◽

Tissue Antigens ◽

Cell Anergy ◽

Deficient Mice

Perinatal T cells broadly access nonlymphoid tissues, where they are exposed to sessile tissue antigens. To probe the outcome of such encounters, we examined the defective elimination of self-reactive clones in Aire-deficient mice. Nonlymphoid tissues were sequentially seeded by distinct waves of CD4+ T cells. Early arrivers were mostly Foxp3+ regulatory T (T reg) cells and metabolically active, highly proliferative conventional T cells (T conv cells). T conv cells had unusually high expression of PD-1 and the IL-33 receptor ST2. As T conv cells accumulated in the tissue, they gradually lost expression of ST2, ceased to proliferate, and acquired an anergic phenotype. The transition from effector to anergic state was substantially faster in ST2-deficient perinates, whereas it was abrogated in IL-33–treated mice. A similar dampening of anergy occurred after depletion of perinatal T reg cells. Attenuation of anergy through PD-1 blockade or IL-33 administration promoted the immediate breakdown of tolerance and onset of multiorgan autoimmunity. Hence, regulating IL-33 availability may be critical in maintaining T cell anergy.

Download Full-text

CD40-Activated B-Cell Chronic Lymphocytic Leukemia Cells for Tumor Immunotherapy: Stimulation of Allogeneic Versus Autologous T Cells Generates Different Types of Effector Cells

Blood ◽

10.1182/blood.v93.6.1992.406k23_1992_2002 ◽

1999 ◽

Vol 93 (6) ◽

pp. 1992-2002 ◽

Cited By ~ 113

Author(s):

Raymund Buhmann ◽

Annette Nolte ◽

Doreen Westhaus ◽

Bertold Emmerich ◽

Michael Hallek

Keyword(s):

T Cells ◽

T Cell ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Tumor Antigens ◽

Lymphocytic Leukemia ◽

T Cell Anergy ◽

Cell Anergy ◽

Cell Chronic Lymphocytic Leukemia ◽

Stimulation Of

Although spontaneous remissions may rarely occur in B-cell chronic lymphocytic leukemia (B-CLL), T cells do generally not develop a clinically significant response against B-CLL cells. Because this T-cell anergy against B-CLL cells may be caused by the inability of B-CLL cells to present tumor-antigens efficiently, we examined the possibility of upregulating critical costimulatory (B7-1 and B7-2) and adhesion molecules (ICAM-1 and LFA-3) on B-CLL cells to improve antigen presentation. The stimulation of B-CLL cells via CD40 by culture on CD40L expressing feeder cells induced a strong upregulation of costimulatory and adhesion molecules and turned the B-CLL cells into efficient antigen-presenting cells (APCs). CD40-activated B-CLL (CD40-CLL) cells stimulated the proliferation of both CD4+ and CD8+ T cells. Interestingly, stimulation of allogeneic versus autologous T cells resulted in the expansion of different effector populations. Allogeneic CD40-CLL cells allowed for the expansion of specific CD8+cytolytic T cells (CTL). In marked contrast, autologous CD40-CLL cells did not induce a relevant CTL response, but rather stimulated a CD4+, Th1-like T-cell population that expressed high levels of CD40L and released interferon-γ in response to stimulation by CD40-CLL cells. Together, these results support the view that CD40 activation of B-CLL cells might reverse T-cell anergy against the neoplastic cell clone, although the character of the immune response depends on the major histocompatibility complex (MHC) background on which the CLL or tumor antigens are presented. These findings may have important implications for the design of cellular immunotherapies for B-CLL.

Download Full-text

Ligation of CD137 receptor prevents and reverses established anergy of CD8+ cytolytic T lymphocytes in vivo

Blood ◽

10.1182/blood-2003-06-2184 ◽

2004 ◽

Vol 103 (1) ◽

pp. 177-184 ◽

Cited By ~ 68

Author(s):

Ryan A. Wilcox ◽

Koji Tamada ◽

Dallas B. Flies ◽

Gefeng Zhu ◽

Andrei I. Chapoval ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Molecular Mechanisms ◽

Transplant Rejection ◽

Critical Role ◽

Tumor Necrosis Factor Receptor ◽

T Cell Anergy ◽

Cell Anergy ◽

Induced Tolerance

Abstract T-cell anergy is a tolerance mechanism defined as a hyporesponsive status of antigen-specific T cells upon prior antigen encounter and is believed to play a critical role in the evasion of tumor immunity and the amelioration of allogeneic transplant rejection. Molecular mechanisms in controlling T-cell anergy are less known. We show here that administration of an agonistic monoclonal antibody (mAb) to CD137, a member of the tumor necrosis factor receptor superfamily, prevents the induction of CD8+ cytolytic T-lymphocyte (CTL) anergy by soluble antigens. More importantly, CD137 mAb restores the functions of established anergic CTLs upon reencountering their cognate antigen. As a result, infusion of CD137 mAb inhibits progressive tumor growth that is caused by soluble tumor antigen-induced tolerance in a P815R model. CD137 mAb also restores proliferation and effector functions of anergic alloreactive 2C T cells in a bone marrow transplantation model. Our results indicate that ligation of CD137 receptor delivers a regulatory signal for T-cell anergy and implicate manipulation of the CD137 pathway as a new approach to break T-cell tolerance.

Download Full-text

Maintenance of CD8+T-cell anergy by CD4+CD25+ regulatory T cells in chronic graft-versus-host disease

Experimental & Molecular Medicine ◽

10.1038/emm.2006.58 ◽

2006 ◽

Vol 38 (5) ◽

pp. 494-501 ◽

Cited By ~ 8

Author(s):

Juyang Kim ◽

Hye J Kim ◽

Woon S Choi ◽

Seok H Nam ◽

Hong R Cho ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Graft Versus Host Disease ◽

Cd8 T Cell ◽

Host Disease ◽

Graft Versus Host ◽

T Cell Anergy ◽

Cell Anergy

Download Full-text

T-cell anergy: a consequence of interaction between T cells and allogeneic rat renal epithelial cells

Transplant International ◽

10.1111/j.1432-2277.1994.tb01444.x ◽

1994 ◽

Vol 7 (s1) ◽

pp. 563-566

Author(s):

M. R. Rajasekar ◽

G. Proud ◽

R. M. R. Taylor ◽

J.A. Kirby ◽

M. R. Rajasekar ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Epithelial Cells ◽

Renal Epithelial Cells ◽

T Cell Anergy ◽

Cell Anergy

Download Full-text

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.

Download Full-text