Acquired thymic tolerance: Role of CTLA4 in the initiation and maintenanceof tolerance in a clinically relevant autoimmune disease model

Injection of Ag into the thymus of adult animals induces specific systemic tolerance, The mechanisms of acquired thymic tolerance include anergy and t he deletion of Ag-specific T cells. Here, we report that anergy to nominal Ag induced via acquired thymic tolerance requires CTL-associated Ag 4 (CTLA 4) engagement, The role of CTLA4 in the induction and maintenance of tolera nce was then investigated in the murine experimental autoimmune encephalomy elitis model. CTLA4 blockade abrogated the induction but not the maintenanc e phase of acquired thymic tolerance induced by intrathymic injection of my elin Ags, In addition, CTLA4 blockade had a restricted window of action aft er priming with Ag, which is consistent with the expression patterns of CTL A4 in vivo. We conclude that: 1) the induction of acquired thymic tolerance requires signaling through CTLA4 and 2) CTLA4 does not appear to be requir ed for the maintenance of acquired thymic tolerance. This is the first repo rt documenting the role of a CTLA4 negative signaling pathway in the induct ion of tolerance in an autoimmune disease model.