Regulation of thymic type I IFN expression and its role in T cell development

Abstract

Abstract Thymocytes undergo a complex maturation process after being positively selected. Recently, the involvement of type I IFN signaling during these late stages was suggested; however, the regulation of intra-thymic type I IFN production and its role in T cell development and central tolerance are relatively unknown. We found that type I IFN, especially IFN-beta, regulate the expression of the maturation marker Qa2, the transcription factor STAT1 and the cell surface protein Ly6A in mature thymocytes. Using a published luciferase reporter mouse strain, Ifnbluc, we found that IFN-beta is expressed in the thymus in the steady state, and its levels peak at around 2–3 weeks of age, when the expression quickly returns to basal levels. The cell source of IFN-beta was mainly medullary thymic epithelial cells (mTEC) expressing high levels of MHC-II and CD80. We showed that IFN-beta expression on mTEC was completely dependent on AIRE and partially dependent on RANKL and CD40 signaling pathways. Additionally, we evaluated the impact of thymic IFN-beta expression on T cell tolerance. Our data suggest that T cells from mice lacking IFN-beta or AIRE show a higher reactivity to IFN-stimulated antigen presenting cells compared to T cells from wild-type mice. We hypothesize that thymic type I IFN provide a mechanism to promote T cell tolerance to IFN-induced peptides.