Pinpointing when T cell costimulatory receptor CTLA-4 must be engaged to dampen diabetogenic T cells

Abstract

Engagement of the T cell costimulatory receptor CTLA-4 can potently down-regulate an immune response. For example, in a T cell receptor transgenic mouse model of autoimmune diabetes, CTLA-4 interactions keep pancreatic islet-reactive T cells in check, evidenced by the finding that mAb blockade of CTLA-4 rapidly provokes diabetes in animals that would not normally succumb until many months later. Interestingly, this effect is only observed early in the course of disease, before insulitis is stably entrenched. Here, we have exploited a highly synchronous and easily manipulable transfer system to determine precisely when CTLA-4 must be engaged to check the diabetogenicity of islet-reactive T cells. Our results indicate that CTLA-4 interactions during initial priming of the T cells in the pancreatic lymph nodes are not determinant. Rather, the critical interactions occur when the T cells secondarily reencounter their antigen in the target organ, the pancreatic islets. In addition, we made use of CTLA-4-deficient mice to bolster our interpretation that CTLA-4 engagement has a dampening rather than an enhancing influence on diabetes progression. autoimmunity ͉ diabetes ͉ costimulatory molecules ͉ T cell activation ͉ T cell regulation C TLA-4 (CD152) is an important regulator of the immune response (1, 2). It is a member of a growing family of costimulatory receptors specifically expressed on the surface of T cells. It and its closest homologue, CD28, bind to the B7-1 and B7-2 (CD80 and CD86, respectively) costimulatory ligands displayed primarily on antigen-presenting cells (3). Some reports have suggested that CTLA-4, like CD28, acts as a positive costimulator, transmitting a signal that somehow synergizes with the signal delivered through the T cell receptor (TCR) to promote T cell stimulation (4-6). However, the large majority of data argues for an opposing role, as a dampener of T cell activation. CTLA-4 blockade enhances T cell responses in vitro (7-16) and in vivo (16-23), augments antitumor immunity (24-26), and exacerbates autoimmune disease (27-29). In addition, mice carrying a CTLA-4-null mutation show massive accumulation of activated T cells in the peripheral lymphoid organs and leukocyte infiltration into a variety of tissues (30-32).It is not yet clear precisely when, during an immune response, CTLA-4 must be engaged to exert its down-regulatory function. Given the difficulty of detecting it on the surface of naive T cells, and its up-regulation on T cell activation, it originally was proposed that CTLA-4 would act late in a response. There are certainly indications that this can occur (12,28,(33)(34)(35)(36)(37). However, there are also examples of it acting early, to set the tone of a response (9, 10, 17, 29, 34-36, 38, 39).We have focused on this issue by exploiting the synchrony and manipulability of a recently described transfer system (40) derived from the BDC2.5 TCR transgenic (tg) mouse model of autoimmune diabetes (41). BDC2.5 TCR tg mice carry the rearranged TCR-␣ and TCR-␤ genes from a CD4 ϩ ,...

CTLA-4 Differentially Regulates T Cell Responses to Endogenous Tissue Protein Versus Exogenous Immunogen

“…It also parallels recent studies on CD8 T cells specific for pancreatic-expressed Ag that demonstrate that quantitative differences in CTL precursors can affect qualitative parameters of a response, for example, the dependence on CD4 help (27). The conversion of the relatively innocuous peri-islet infiltration into aggressive infiltration by eliminating CTLA-4 function is consistent with previously published work using another TCR transgenic system (28).…”

Stat Signals Release Activated Naive Th Cells from an Anergic Checkpoint

“…In the absence of Stat signals, activated T cells remain arrested by CTLA-4 in an anergic state, thus preventing the mischievous development of an unregulated effector response. Indeed, competent signals provided in inappropriately inflamed tissues might release the anergic program established within pre-activated cell populations and contribute to the development of autoimmunity (59).…”

Paradoxical Dampening of Anti-Islet Self-Reactivity but Promotion of Diabetes by OX40 Ligand

“…2) and A. Herman et al, manuscript in preparation). Nor did the OK40L KO mutation accelerate disease on the BDC2.5/N background as the CTLA-4 mutation does (39). With this result then, OX40L acts as a positive costimulator.…”