Thymic Interferon Impacts T Cell Selection

Abstract Autoimmune diseases are triggered by the loss of immunological tolerance to self-antigens. Although previous work has characterized mechanisms driving immune tolerance to tissue restricted self-antigens, less is understood about how tolerance is established for inflammation-associated self-antigens that are expressed transiently during acute infection. This is particularly important with the discovery that autoantibodies to type I interferons (IFN) are commonly found in elderly individuals, and predispose to severe COVID19. Recent work from several groups has found that Type I and Type III IFN are expressed in the thymus at steady state (in the absence of infection) and drive expression of interferon stimulated genes in antigen presenting cells and developing thymocytes. We hypothesize that IFN is present in the thymus in order to tolerize developing T cells to self-antigens presented during acute infection (such as those derived from interferon and interferon stimulated genes.) In line with this, T cell receptor (TCR) repertoire analysis showed that mice lacking the type I IFN receptor (Ifnar KO) have distinct T conventional (Tconv) and T regulatory (Treg) TCR repertoires from wild type (WT) mice. We have identified two groups of interesting receptors from this TCR repertoire analysis; 1) IFN-deleted receptors(~50 TCRs) that are present in the Ifnar KO Tconv repertoire and absent from the WT repertoire, and 2) IFN-dependent Treg receptors(~750 TCRs) that are present in the WT Treg repertoire but lost from the Ifnar KO Treg repertoire. We have expressed TCRs from each group in hybridomas and retrogenic mice in order to determine the specificity of these TCRs and characterize the development of thymocytes expressing them. Supported by grants from NIH (T32 AI007313)