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 highdose peripheral T cell tolerance is mediated by anergy or deletion and ispreceded by T cell activation. Co-stimulatory molecules B7-1 (CD80)/B7-2(CD86) and their counter-receptors CD28/CTLA-4 play pivotal roles in T cellactivation and immune regulation. In the present study, we examined theroles of the B7 co-stimulation pathway in the generation of high doseperipheral T cell tolerance. We found that blocking B7:CD28/CTLA-4interaction at the time of tolerance induction partially prevented T celltolerance, whereas selective blockade of B7:CTLA-4 interaction completelyabrogated peripheral T cell tolerance induced by either oral or i.p.antigens. These results suggest that CTLA-4-mediated feedback regulationplays a crucial role in the induction of high dose peripheral T celltolerance.