LYMPHOPROLIFERATION IN CTLA-4-DEFICIENT MICE IS MEDIATED BY COSTIMULATION-DEPENDENT ACTIVATION OF CD4(-CELLS() T)

CTLA-4-deficient animals develop a fatal lymphoproliferative disorder. The cellular mechanism(s) responsible for this phenotype have not bee n determined. Here, we show that there is a preferential expansion of CD4(+) T cells in CTLA-4(-/-) mice, which results in a skewing of the CD4/CD8 T cell ratio. In vivo antibody depletion of CD8(+) T cells fro m birth does not alter the onset or the severity of the CD28-dependent lymphoproliferative disorder. In contrast, CD4(+) T cell depletion co mpletely prevents all features characteristic of the lymphoproliferati on observed in CTLA-4-deficient mice. These results demonstrate that C D4(+) T cells initiate the phenotype in the CTLA-4(-/-) mice. Further, these results suggest that the role of CTLA-4 in peripheral CD4(+) ve rsus CD8(+) T cell homeostasis is distinct.