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

Abstract

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 ablation of the NF-κB–inducing kinase (NIK) in the TEC compartment. In contrast to germline-deficient <i>NIK^−/−</i> mice, <i>Foxn1</i>^Cre<i>NIK</i>^fl/fl mice rapidly developed fatal T cell–dependent multiorgan autoimmunity shortly after birth. Thymic transplantation and adoptive 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.