T-cell receptor ligation by peptide/MHC induces activation of a caspase in immature thymocytes: The molecular basis of negative selection

T-cell receptors (TCRs) are created by a stochastic gene rearrangement process during thymocyte development, generating thymocytes bearing useful, as well as unwanted, specificities, Within the latter group, autoreactive thymocytes arise which are subsequently eliminated via a thymocyte-specific apoptotic mechanism, termed negative selection, The molecular basis of this deletion is unknown. Here, we show that TCR triggering by peptide/MHC ligands activates a caspase in double-positive (DP) CD4(+)CD8(+) thymocytes, resulting in their death, Inhibition of this enzymatic activity prevents antigen-induced death of DP thymocytes in fetal thymic organ culture (FTOC) from TCR transgenic mice as well as apoptosis induced by anti-CD3 epsilon monoclonal antibody and corticosteroids in FTOC of normal C57BL/6 mice, Hence, a common caspase mediates immature thymocyte susceptibility to cell death.