Protection against autoimmunity is driven by thymic epithelial cell–mediated regulation of Treg development

摘要

Medullary thymic epithelial cells (mTECs) are key antigen-presenting cells mediating T cell tolerance to prevent harmful autoimmunity. mTECs both negatively select self-reactive T cells and promote the development of thymic regulatory T cells (tT_(regs)) that mediate peripheral tolerance. The relative importance of these two mechanisms of thymic education to prevent autoimmunity is unclear. We generated a mouse model to specifically target the development and function of mTECs by conditional ablationof the NF-κB–inducing kinase (NIK) in the TEC compartment. In contrast to germline-deficient NIK~(-/-) mice, Foxn1~(Cre)NIK~(fl/fl) mice rapidly developed fatal T cell–dependent multiorgan autoimmunity shortly after birth. Thymic transplantation andadoptive transfer experiments demonstrated that autoimmunity arises specifically from the emergence of dysfunctional tT_(regs). Thus, T_(reg) function, rather than negative selection, enforces the protection of peripheral tissues from autoimmune attack.