Informal Seminar - Matouš Vobořil

"Thymflammation: A novel concept of central immune tolerance"

Central immune tolerance relies on the thymus to eliminate self-reactive T cells and generate regulatory T cells (Tregs), preventing autoimmunity. While this process is well described for tissue-restricted self-antigens presented by medullary thymic epithelial cells, how the immune system establishes tolerance to antigens expressed only during inflammation, such as interferon-stimulated genes (ISGs) or cytokine-regulated proteins, has remained unclear. Here I present the concept of "thymflammation": the thymus maintains a state of sterile inflammation to enable T cell selection against inflammation-associated self-antigens.

We show that medullary thymic epithelial cells produce type I and III interferons (IFNs) in a sterile, Aire-dependent manner, driving ISG expression in thymic antigen-presenting cells. Loss of IFN signaling impairs Treg generation, reduces TCR repertoire diversity, and compromises tolerance to ISG-derived antigens. We further identify a CD301b⁺ dendritic cell population maintained by steady-state IL-4/IL-13 that mediates clonal deletion, establishing tolerance to type-2-inflammation-associated antigens. Finally, we describe a novel CX3CR1⁺ transitional DC subset that continuously immigrates into the thymus from the blood, positioned near thymic microvessels, and is uniquely capable of acquiring and presenting peripheral antigens.

Together, these findings support a model in which the thymus mirrors peripheral inflammatory environments to tolerize T cells against context-dependent self-antigens, with broad implications for autoimmunity.

Faculty Host: Ellen Rothenberg