CTLA-4 suppresses the pathogenicity of self antigen–specific T cells by cell-intrinsic and cell-extrinsic mechanisms

Abstract

CTLA-4 is critical in maintaining self-tolerance but the mechanisms of its actions have been controversial. Here, we examined the antigen-specificity of tissue-infiltrating CD4+ T cells in CTLA-4−/− mice and determined the in vivo cellular targets of CTLA-4. Tissue-infiltrating CTLA-4−/− T cells exhibited TCR-dependent homing to their tissues of origin, suggesting reactivity against tissue-specific antigens. We identified the pancreas-specific enzyme Pdia2 as an autoantigen in CTLA-4−/− mice. CTLA-4 expressed either on Pdia2-specific effector cells, or on Tregs, was sufficient to control tissue destruction mediated by Pdia2-specific T cells. These results demonstrate that both cell-intrinsic and cell non-autonomous action of CTLA-4 operate in the context of regulation of an authentic self-antigen for which CTLA-4 is required to maintain tolerance.

Role of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 on apoptosis-Prone CD8 T cells in persistent hepatitis B virus infection

“…These data are in line with recent demonstrations that CTLA-4 plays a critical role in the effector T-cell compartment in addition to its contribution to regulatory T-cell function. 15,16 CTLA-4 mediated inhibition may depend on the fact that it shares ligands (B7-1 and B7-2) with CD28 but has higher avidity; when the supply of these ligands is limited, CTLA-4-mediated inhibitory signaling could override CD28-mediated positive costimulation. In CHB, the ability of CTLA-4 to outcompete CD28 may be favored not only by the increase in CTLA-4, but also by the reduced levels of CD28 on CD8 T cells 17 and by the scarcity of B7 ligands on hepatocytes and other intrahepatic cells with antigen-presenting capability.…”

“…Recent work has highlighted the critical role for CTLA-4-expressing antigen-specific effector T cells in regulating peripheral tolerance after secondary encounter with antigen in target tissues. 15 Restoration of effective antiviral immunity through blockade of CTLA-4 may therefore be at the expense of control of collateral tissue damage, emphasizing the need for a targeted therapeutic approach. 25 In summary, we demonstrate a contributory role for CTLA-4 in driving Bim-dependent apoptosis of the antiviral response in CHB.…”

Cutting Edge: CTLA-4 on Effector T Cells Inhibits In Trans

“…Indeed, Treg-specific CTLA-4 deficiency results in decreased suppressive function and causes disease, albeit milder than seen in mice fully deficient in CTLA-4 (17). Blockade of CTLA-4 on both effector T cells and Tregs contributes to antitumor immunity (18), and a vague consensus has emerged in which CTLA-4 on effector T cells is purported to act cell intrinsically, whereas cell-extrinsic CTLA-4 function is commonly attributed to Tregs (4,19).…”

Rôle de CTLA-4 dans la cosignalisation négative du système immunitaire

“…Par ce biais, les Treg vont réguler l'activation des T conventionnels aux antigènes du soi et de l'environnement. Dans d'autres modèles de tolérance aux antigènes du soi d'origine pancréatique, les molécules CTLA-4 exprimées sur les deux types de lymphocytes, Treg et T conventionnels, collaborent pour préserver la tolérance au soi [26].…”