The presentation of self-antigens to circulating T cells is a critical, precipitating event in the induction of autoimmune injury in parenchymal organs. Epithelia expressing these self-antigens are thought to release such moieties for reprocessing by traditional antigen-presenting cells within the lymphoid system. We now demonstrate, however, that some epithelium possess novel functional mechanisms for presenting their own antigens to a responsive, syngeneic T cell repertoire. The presentation of these self-antigens occurs in the context of MHC class II molecules and depends on CD4 associative-recognition determinants. Our findings strongly suggest that organ epithelium may directly activate cell-mediated events to produce autoimmunity through self-recognition.