Dendritic cell-directed CTLA-4 engagement during pancreatic beta cell antigen presentation delays type 1 diabetes.

ABSTRACT

The levels of expression of alternatively spliced variants of CTLA-4 and insufficient CTLA-4 signaling have been implicated in type 1 diabetes. Hence, we hypothesized that increasing CTLA-4-specific ligand strength on autoantigen-presenting dendritic cells (DCs) can enhance ligation of CTLA-4 on T cells and lead to modulation of autoreactive T cell response. In this study, we show that DC-directed enhanced CTLA-4 engagement upon pancreatic beta cell Ag presentation results in the suppression of autoreactive T cell response in NOD mice. The T cells from prediabetic NOD mice treated with an agonistic anti-CTLA-4 Ab-coated DC (anti-CTLA-4-Ab DC) showed significantly less proliferative response and enhanced IL-10 and TGF-beta1 production upon exposure to beta cell Ags. Furthermore, these mice showed increased frequency of Foxp3+ and IL-10+ T cells, less severe insulitis, and a significant delay in the onset of hyperglycemia compared with mice treated with control Ab-coated DCs. Further analyses showed that diabetogenic T cell function was modulated primarily through the induction of Foxp3 and IL-10 expression upon Ag presentation by anti-CTLA-4-Ab DCs. The induction of Foxp3 and IL-10 expression appeared to be a consequence of increased TGF-beta1 production by T cells activated using anti-CTLA-4-Ab DCs, and this effect could be enhanced by the addition of exogenous IL-2 or TGF-beta1. Collectively, this study demonstrates the potential of a DC-directed CTLA-4 engagement approach not only in treating autoimmunity in type 1 diabetes, but also in altering diabetogenic T cell function ex vivo for therapy.