Peripheral lymphocyte deletion is required for reduction of lymphocyte numbers after expansion in response to antigen. Peripheral deletion is mediated in part by the activation of apoptosis by engagement of the death receptor, Fas (CD95), by its ligand, Fas ligand (FasL; CD95L), among other mechanisms. Here we used T cell receptor (TCR) transgenic animals to examine the role of inducible expression of nonlymphoid FasL in response to peptide antigen. Antigenic challenge of TCR transgenic mice resulted in increased expression of FasL in a number of nonlymphoid tissues including the epithelium of the small intestine. Similar results were obtained in an adoptive transfer system in which TCR transgenic T cells were transferred into recipient animals. The functional relevance of nonlymphoid FasL in peripheral deletion is supported by the observation that FasL-deficient gld animals showed a significantly reduced rate of clearance of transferred antigen-specific lymphocytes, although the lymphocytes themselves were wild type for FasL. These observations were supported further by studies in a transgenic mouse model where lacZ was expressed under the control of the proximal promoter of the FasL gene. Using these transgenic mice, we observed induced activity of the FasL promoter in intestinal epithelial cells throughout the crypts and villi, where we also observed infiltration of activated T cells. These data demonstrate that nonlymphoid FasL is expressed in response to peripheral T cell activation and participates in the regulation of T cells that infiltrate peripheral tissues.