Tissue-specific tolerance of endogenous self antigen-specific CD4+ T cells (IRC4P.484)

Abstract

Abstract CD4+ T cells specific for self antigens are involved in autoimmunity, but little is known about the extent to which these potentially harmful T cells develop within a normal T cell repertoire or how they are maintained in a tolerant state. We modeled Cre recombinase as a neo-self antigen that is expressed by various different tissue-specific promoters in several strains of Cre transgenic mice. We mapped a CD4+ T cell epitope within the Cre protein and generated a corresponding peptide:MHCII tetramer, which we used in a magnetic enrichment strategy to directly detect rare populations of endogenous Cre-specific CD4+ T cells that naturally develop in the unmanipulated immune systems of these mice. We found that deletion of Cre-specific T cells was efficient in mice ubiquitously expressing Cre, but almost nonexistent in mice expressing Cre in tissue-restricted patterns. In mice expressing Cre exclusively in the pancreas, immunization with Cre antigen induced strong Cre-specific T cell expansion and cytokine production, suggesting immune ignorance to the pancreatic self antigen. In contrast, tolerance to Cre self antigen expressed in mucosal tissues such as the gut and lung relied on elevated steady state frequencies of Cre-specific regulatory T cells. While these Tregs efficiently controlled primary autoimmune responses, their ability to maintain tolerance was lost over successive antigenic challenges, indicating limits of peripheral tolerance to tissue-restricted self antigens.