The development of mouse models of human organ-specific autoimmune diseases has been hampered by the need to immunize mice with autoantigens in potent adjuvants. Even autoantigen-specific T cell receptor transgenic models of autoimmunity have proven to be complex as the transgenic mice frequently fail to develop disease spontaneously. We have isolated a CD4(+) T cell clone (TxA23)that recognizes the gastric parietal cell antigen, H/K ATPase alpha-chain(630-641), from a mouse with autoimmune gastritis that developed after thymectomy on day 3 of life. The T cell receptor alpha and beta genes from this clone were used to generate A23 transgenic mice. All A23 transgenic animals spontaneously developed severe autoimmune gastritis, and evidence of disease was detected as early as day 10 of life. Gastritis could be transferred to immunocompromised mice with a limited number of transgenic thymocytes (10(3)), but as many as 10(7) induced only mild disease in wild-type animals. Due to the complete penetrance of spontaneous disease, identity of the auto-antigen, susceptibility to immunoregulation, and close relation to autoimmune gastritis in man, A23 transgenic mice represent a unique CD4(+) T cell-mediated disease model for understanding the multiple factors regulating organ-specific autoimmunity.