The role of a cell death-associated gene, fas, in T lymphocyte development and responses to antigen has been analyzed by breeding a transgenic T cell receptor specific for the W-104 peptide of pigeon cytochrome c into fas-defective MRL-lpr/lpr and control MRL+‘+ mice. Transgene-expresaing T cells mature normally in both strains and populate peripheral lymphoid tissues in normal numbers. Mature CD4+ T cells from the Iprllpr mice are resistant to suppression by high doses of antigen and to apoptotic cell death. In vivo administration of peptide antigen causes deletion of thymic T cells in both MRL-lprllpr and MRL+‘+ strains. By contrast, antigen-induced deletion of peripheral T cells occurs in the MRL+‘+ but not in the MRL-/pr//pr strain. Therefore, the fas gene plays an essential role in activation-induced cell death in mature T lymphocytes, but not in the negative selection of immature cells in the thymus.