Impaired Aire-dependent IFN signaling in the thymus precedes the protective autoantibodies to IFNα.

Recent studies have highlighted the role of the thymus in maintaining immune tolerance to type 1 interferons (T1 IFNs). Individuals with thymic abnormalities, such as autoimmune regulator (AIRE) gene mutations, frequently develop neutralizing autoantibodies to interferon-alpha (IFNα). Unlike mice, Aire-deficient rats develop robust autoantibodies to IFNα. Using this rat model, we show that Aire regulates the thymic expression of interferon-stimulated genes (ISGs), which occurs before developing anti-IFNα autoantibodies. In the periphery, we observed a widespread downregulation of ISGs across immune cells and reduced activation of natural killer (NK) cells. Furthermore, the presence of anti-IFNα autoantibodies correlated with reduced peripheral tissue inflammation, suggesting their role in dampening T1 IFN signaling and minimizing tissue infiltration. Our findings reveal that Aire-mediated regulation of thymic T1 IFN signaling is linked to the production of protective anti-IFNα autoantibodies, which inversely correlate with autoimmune pathology in peripheral tissues.