Blocked negative selection of developing T cells in mice expressing the baculovirus p35 caspase inhibitor

Clonal deletion in the thymus by apoptosis is involved in purging the immun e system of self-reactive T lymphocytes (negative selection). Cysteine prot eases (caspases) belonging to the CPP32 family are activated during this pr ocess. We have produced transgenic mice expressing baculovirus p35, a broad -range caspase inhibitor. Thymocytes from p35 transgenic mice were resistan t in vitro to several apoptosis-inducing agents; this resistance correlated with the inhibition of CPP32-like activity. Negative selection iii vivo of thymocytes triggered by two exogenous antigens, staphylococcal enterotoxin B superantigen and an antigenic peptide in the F5 T-cell receptor transgen ic model, was specifically inhibited in p35 transgenic mice. Our results pr ovide direct evidence for caspase involvement in negative selection during thymocyte development.