Sterile production of interferons in the thymus affects T cell repertoire selection

• Published in: Science immunology 2024-07, Vol.9 (97), p.eadp1139
• Main Authors: Ashby, K Maude, Vobořil, Matouš, Salgado, Oscar C, Lee, S Thera, Martinez, Ryan J, O'Connor, Christine H, Breed, Elise R, Xuan, Shuya, Roll, Charles R, Bachigari, Saumith, Heiland, Hattie, Stetson, Daniel B, Kotenko, Sergei V, Hogquist, Kristin A
• Format: Article
• Language: English
• Subjects: Animals; Interferons - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Antigen, T-Cell - immunology; T-Lymphocytes - immunology; Thymus Gland - immunology
• ISSN: 2470-9468; 2470-9468
• DOI: 10.1126/sciimmunol.adp1139

Type I and III interferons (IFNs) are robustly induced during infections and protect cells against viral infection. Both type I and III IFNs are also produced at low levels in the thymus at steady state; however, their role in T cell development and immune tolerance is unclear. Here, we found that both type I and III IFNs were constitutively produced by a very small number of AIRE murine thymic epithelial cells, independent of microbial stimulation. Antigen-presenting cells were highly responsive to thymic IFNs, and IFNs were required for the activation and maturation of thymic type 1 conventional dendritic cells, macrophages, and B cells. Loss of IFN sensing led to reduced regulatory T cell selection, reduced T cell receptor (TCR) repertoire diversity, and enhanced autoreactive T cell responses to self-antigens expressed during peripheral IFN signaling. Thus, constitutive exposure to IFNs in the thymus is required for generating a tolerant and diverse TCR repertoire.