Thymflammation: The Role of a Constitutively Active Inflammatory Network and “Ectopic” Cell Types in the Thymus in the Induction of T Cell Tolerance and Beyond

The thymus exhibits constitutive activation of nearly all major inflammatory pathways, including sterile MyD88-dependent signaling and interferon production by mTECs, the presence of cellular and molecular components of type 1, type 2, and type 3 responses, as well as sustained B cell activation. The reasons for the existence of such a complex constitutively active inflammatory network at the site of T cell development—where the initial pathogen encounter is unlikely—have remained enigmatic. We propose that this inflammatory thymic ‘ecosystem’ has evolved to promote immunological tolerance to ‘inflammatory self’—endogenous molecules absent from most peripheral tissues at steady state but upregulated during pathogen invasion. The spatial and temporal overlap with pathogen presence makes the discrimination of the inflammatory self from pathogen-derived molecules a unique challenge for the adaptive immune system. The frequent occurrence of diseases associated with autoantibodies against proinflammatory cytokines underscores the persistent risk of these molecules being misidentified as foreign. Their abundant representation in the thymus, therefore, is likely to be critical for maintaining tolerance. This review explores current insights into the thymic inflammatory network, its cellular and molecular constituents, and their role in the induction of T cell tolerance.