Thymic Interferons: A Little Goes a Long Way

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.