Characterizing the role of thymic interferon in T cell development and selection

Abstract

Type I and III interferons (IFNs) are robustly induced during infections, where they protect cells against viral infection and activate immune cells. Curiously, both type I and type III IFNs were reported to be produced at low levels in the thymus in the absence of infection – the site of T cell development and a crucial organ for immune tolerance.To understand the impact of IFNs on T cell development and immune tolerance, we identified the cells that produce and respond to IFN. We found that both type I and III IFNs were constitutively produced by a very small number of AIRE+ 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 DC1, macrophages and B cells. Loss of IFN-sensing led to reduced T regulatory 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 interferons in the thymus is required for generating a safe and diverse TCR repertoire. Furthermore, recent reports have identified strongly IFN-signaled populations of mature naïve T cells in the periphery, suggestive of unappreciated heterogeneity within the naïve T cell pool. In light of these findings, we were curious to determine whether type I IFN signaling in the thymus impacted T cell fate. To this end, we used Mx1-lineage tracing mice, in which Cre- expression is controlled by the IFN-responsive Mx1 promoter, to track IFN experienced T cells.