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Anergy Induction (anergy + induction)

Distribution by Scientific Domains

Medical Sciences	100%

Selected Abstracts

c-Rel phenocopies PKC, but not Bcl-10 in regulating CD8+ T-cell activation versus tolerance,

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2010
Elissa K. Deenick
Abstract Elucidating the signaling events that promote T-cell tolerance versus activation provides important insights for manipulating immunity in vivo. Previous studies have suggested that the absence of PKC, results in the induction of anergy and that the balance between the induction of the transcription factors NFAT, AP1 and NF-,B plays a key role in determining whether T-cell anergy or activation is induced. Here, we examine whether Bcl-10 and specific family members of NF-,B act downstream of PKC, to alter CD8+ T-cell activation and/or anergy. We showed that T cells from mice deficient in c-Rel but not NF-,B1 (p50) have increased susceptibility to the induction of anergy, similar to T cells from PKC,-deficient mice. Surprisingly T cells from Bcl-10-deficient mice showed a strikingly different phenotype to the PKC,-deficient T cells, with a severe block in TCR-mediated activation. Furthermore, we have also shown that survival signals downstream of NF-,B, are uncoupled from signals that mediate T-cell anergy. These results suggest that c-Rel plays a critical role downstream of PKC, in controlling CD8+ T-cell anergy induction. [source]

CD28 and CTLA-4 coreceptor expression and signal transduction

IMMUNOLOGICAL REVIEWS, Issue 1 2009
Christopher E. Rudd
Summary:, T-cell activation is mediated by antigen-specific signals from the TCR,/CD3 and CD4,CD8,p56lck complexes in combination with additional co-signals provided by coreceptors such as CD28, inducible costimulator (ICOS), cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death (PD-1), and others. CD28 and ICOS provide positive signals that promote and sustain T-cell responses, while CTLA-4 and PD-1 limit responses. The balance between stimulatory and inhibitory co-signals determines the ultimate nature of T-cell responses where response to foreign pathogen is achieved without excess inflammation and autoimmunity. In this review, we outline the current knowledge of the CD28 and CTLA-4 signaling mechanisms [involving phosphatidylinositol 3 kinase (PI3K), growth factor receptor-bound protein 2 (Grb2), Filamin A, protein kinase C , (PKC,), and phosphatases] that control T-cell immunity. We also present recent findings on T-cell receptor-interacting molecule (TRIM) regulation of CTLA-4 surface expression, and a signaling pathway involving CTLA-4 activation of PI3K and protein kinase B (PKB)/AKT by which cell survival is ensured under conditions of anergy induction. [source]

Modulation of immune response with cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin-induced anergic T cells in chronic idiopathic thrombocytopenic purpura,

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 1 2008
X.-L. ZHANG
Summary.,Background:,Platelet glycoprotein (GP)-reactive CD4+ T cells are essential for the stimulation and maintenance of antiplatelet autoantibody production in chronic idiopathic thrombocytopenic purpura (ITP). Blocking costimulatory signals could result in platelet-specific T-cell anergy. Methods:,GP-specific CD4+ T cells from patients with ITP were made anergic using cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin (CTLA4-Ig). The CTLA4-Ig-induced GP-specific anergic T cells were investigated for their inhibitory function on GP-reactive T-cell proliferation and antibody production with in vitro culture systems. To further analyze their tolerizing mechanisms, we cocultured GP-anergic T cells with dendritic cells (DCs) from patients with ITP. Results:,Our studies demonstrated that the anergized GP-specific T cells have profound effects on both GP-specific T-cell proliferation and antibody production. These anergic T cells exerted their suppressive effects mainly in a cell contact-dependent manner, and they were not constitutively suppressive but required specific antigen stimulation to make DCs tolerogenic. The anergic T-cell-modulated DCs could induce the autoreactive T cells to be tolerant, and this effect was not restricted to T cells of the same specificity. Conclusion:,Our studies demonstrate the efficacy of CTLA4-Ig in suppressing the pathologic autoimmune responses in ITP. These findings provide new insights into the underlying mechanisms of anergy induction in chronic ITP. [source]

Tolerization with Hsp65 induces protection against adjuvant-induced arthritis by modulating the antigen-directed interferon-,, interleukin-17, and antibody responses

ARTHRITIS & RHEUMATISM, Issue 1 2009
Shailesh R. Satpute
Objective Pretreatment of Lewis rats with soluble mycobacterial Hsp65 affords protection against subsequent adjuvant-induced arthritis (AIA). This study was aimed at unraveling the mechanisms underlying mycobacterial Hsp65,induced protection against arthritis, using contemporary parameters of immunity. Methods Lewis rats were given 3 intraperitoneal injections of mycobacterial Hsp65 in solution prior to the initiation of AIA with heat-killed Mycobacterium tuberculosis. Thereafter, mycobacterial Hsp65,specific T cell proliferative, cytokine, and antibody responses were tested in tolerized rats. The roles of anergy and the indoleamine 2,3 dioxygenase (IDO),tryptophan pathway in tolerance induction were assessed, and the frequency and suppressive function of CD4+FoxP3+ Treg cells were monitored. Also tested was the effect of mycobacterial Hsp65 tolerization on T cell responses to AIA-related mycobacterial Hsp70, mycobacterial Hsp10, and rat Hsp65. Results The AIA-protective effect of mycobacterial Hsp65,induced tolerance was associated with a significantly reduced T cell proliferative response to mycobacterial Hsp65, which was reversed by interleukin-2 (IL-2), indicating anergy induction. The production of interferon-, (but not IL-4/IL-10) was increased, with concurrent down-regulation of IL-17 expression by mycobacterial Hsp65,primed T cells. Neither the frequency nor the suppressive activity of CD4+FoxP3+ T cells changed following tolerization, but the serum level of anti,mycobacterial Hsp65 antibodies was increased. However, no evidence was observed for a role of IDO or cross-tolerance to mycobacterial Hsp70, mycobacterial Hsp10, or rat Hsp65. Conclusion Tolerization with soluble mycobacterial Hsp65 leads to suppression of IL-17, anergy induction, and enhanced production of anti,mycobacterial Hsp65 antibodies, which play a role in protection against AIA. These results are relevant to the development of effective immunotherapeutic approaches for autoimmune arthritis. [source]