UCSF

Clonal diversity within the adaptive immune system, while endowing organisms with the ability to respond to a broad range of potential pathogens, presents a substantial risk for autoimmunity. Numerous complementary mechanisms have evolved to prevent such deleterious outcomes, and to establish and maintain appropriate tolerance to self. Medullary epithelial cells of the thymus play an essential role in this process by displaying a diverse set of tissue-specific antigens via a mechanism dependent on the Autoimmune regulator (Aire) gene. Here we describe a discrete population of extrathymic Aire-expressing cells (eTACs) in the secondary lymphoid organs. We show that Aire regulates a diverse range of tissue-specific antigen genes in eTACs distinct from those presented in the thymus. To define a potential role for this population in immune tolerance, we demonstrate that self-antigen expression in eTACs is sufficient to prevent T cell-mediated autoimmune diabetes mediated by CD4+ or CD8+ T cells. We demonstrate that such tolerance is established via anergic or deletional mechanisms for CD4+ or CD8+ cells, respectively, and does not require the presence or induction of regulatory populations. Further, we show that tolerance induction by eTACs is highly resistant to conversion to immunogenicity. Finally, we describe the development of a novel transgenic mouse model for depletion of mTECs and eTACs, and suggest that the absence of these populations predisposes to autoimmunity. Together this work identifies self-antigen expressing eTACs as a population with potential significance in both physiologic and therapeutic maintenance of self-tolerance.