CTLA-4 IS REQUIRED FOR THE INDUCTION OF HIGH-DOSE ORAL TOLERANCE

Mucosal and systemic administrations of high dose antigens induce long -lasting peripheral T cell tolerance. We and others have shown that hi gh dose peripheral T cell tolerance is mediated by anergy or deletion and is preceded by T cell activation. Go-stimulatory molecules B7-1 (C D80)/B7-2 (CD86) and their counter-receptors CD28/CTLA-4 play pivotal roles in T cell activation and immune regulation. In the present study , we examined the roles of the B7 co-stimulation pathway in the genera tion of high dose peripheral T cell tolerance. We found that blocking B7:CD28/CTLA-4 interaction at the time of tolerance induction partiall y prevented T cell tolerance, whereas selective blockade of B7:CTLA-4 interaction completely abrogated peripheral T cell tolerance induced b y either oral or i.p. antigens. These results suggest that CTLA-4-medi ated feedback regulation plays a crucial role in the induction of high dose peripheral T cell tolerance.