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

Description Thymic education of regulatory T cells is more important than negative selection in the prevention of autoimmunity. Tolerance enforcement by thymic Tregs A core function of the thymus is protecting the rest of the body from autoimmunity triggered by activation of self-reactive T cells in the periphery. Both deletion of autoreactive clones during T cell repertoire selection and induction of thymic regulatory T cells (tTregs) help achieve suppression of peripheral self-reactivity. Haftmann et al. developed a mouse model in which the tolerance-promoting functions of the thymic epithelium were compromised leading to fatal multiorgan autoimmunity. Foxp3-expressing Tregs in these mice were abnormally activated and compromised in their regulatory activity. Thymic transplantation experiments revealed that a wild-type thymus producing normal tTregs could prevent the autoimmune syndrome initiated by a mutant thymus. These findings suggest that Tregs play a more important role than negative selection in providing protection from autoimmunity. 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 (tTregs) 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 NIK−/− mice, Foxn1CreNIKfl/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 tTregs. Thus, Treg function, rather than negative selection, enforces the protection of peripheral tissues from autoimmune attack.