CTLA-4 (CD152) can inhibit T cell activation by two different mechanisms depending on its level of cell surface expression

CTLA-4 (CD152) engagement results in down-regulation of T cell activation. Two mechanisms have been postulated to explain CTLA-4 inhibition of T cell activation: negative signaling and competitive antagonism of CD28:B7-mediat ed costimulation, We assessed the contributions of these two mechanisms usi ng a panel of T cell lines expressing human CTLA-4 with mutations in the cy toplasmic region. Under conditions of B7-independent costimulation, inhibit ion of IL-2 production following CTLA-4 engagement required the CTLA-4 cyto plasmic region. In contrast, under B7-dependent costimulation, inhibition o f IL-2 production by CTLA-4 engagement was directly proportional to CTLA-4 cell surface levels and did not require its cytoplasmic region. Thus, CTLA- 4 down-regulates T cell activation by two different mechanisms-delivery of a negative signal or B7 sequestration-that are operational depending on the levels of CTLA-4 surface expression. These two mechanisms may have distinc t functional outcomes: rapid inhibition of T cell activation or induction o f T cell anergy.