Thymic Interferons: A Little Goes a Long Way

ABSTRACT Central tolerance is an essential process that protects the mammalian immune system from developing autoimmune reactions by forming a self‐tolerant repertoire of T cells. The extent of central tolerance depends on the diversity of self‐peptide–major histocompatibility complexes that thymocytes encounter on thymic antigen‐presenting cells (APCs). Decades of research have demonstrated that medullary thymic epithelial cells (mTECs), a unique type of APC of stromal origin, possess an extraordinary capacity to produce and present thousands of self‐peptides to developing thymocytes. This ability is facilitated by various unconventional mechanisms, including AIRE‐regulated promiscuous gene expression, mimicry of peripheral cell types, and cooperative antigen transfer between different thymic APCs. Recently, several studies have reported that mTECs and other thymus‐resident cells also produce tonic inflammatory signaling, which shapes the thymic microenvironment and expands the repertoire of presented inflammation‐associated self‐antigens (ISA). In this review, we focus on thymic interferons (IFNs), pro‐inflammatory molecules produced as self‐antigens by mTECs. Beyond their role as rare self‐antigens critical for tolerance induction, IFNs influence the thymic microenvironment by promoting sterile inflammation, regulating the maturation of thymic APCs, and shaping T cell selection. We will discuss the production and regulation of thymic IFNs and their role in APC maturation and T cell selection.