Inducible costimulator-dependent IL-10 production by regulatory T cells specific for self-antigen.

In this study, we investigated the relationship between the expression levels of self-antigen and the function of self-reactive T cells in the periphery. To this end, we used two rat insulin promoter-ovalbumin (RIP-OVA) transgenic mice (RIP-OVA(high), RIP-OVA(low)) in which was produced only in pancreatic beta-islet cells. The OVA-producing transgenic mice were crossed to DO.11.10 (DO) mice expressing a T cell antigen receptor specific for OVA(323-339). The responsiveness of peripheral CD4(+) T cells in the double transgenic mice was examined. We demonstrated that hyporesponsive but highly IL-10-producing T cells were developed in DO x OVA(high) mice only, not in DO x OVA(low) mice. These IL-10-producing T cells exhibited regulatory activity both in in vitro and in vivo experiments. Moreover, these IL-10-producing regulatory T (Tr) cells expressed high levels of inducible costimulator (ICOS) before in vitro stimulation. Blockade of ICOS-signaling inhibited the production of IL-10 and abrogated the inhibitory function of these Tr cells. Thus, these results suggested that the development of IL-10-producing Tr cells depends on the expression levels of self-antigen in vivo and that ICOS signal plays a critical role in immune regulation by IL-10-producing Tr cells in self-tolerance.