AIRE drives early life thymic interferons and changes thymic self-antigen expression [bulk RNA-seq]

Type I interferons (IFN-I) are transiently induced during infections, but were reported to be produced in the thymus at steady state. We found that developing thymocytes displayed an IFN-I signature that was mainly dependent on IFN-β. Using Ifnb1 reporter mouse strains, we observed IFN-β expression in a small population of medullary thymic epithelial cells (mTEC), which was AIRE-dependent and peaked at 2-3 weeks of age. To study the cellular response to thymic IFN, we used a Mx1gfp reporter mouse strain and found that the IFN response in T cells and myeloid cells was abrogated by IFNaR deficiency, whereas the response in B cells and dendritic cells was dependent on both IFNaR and IFNlR. Furthermore, single-cell RNAseq analysis revealed dramatic transcriptional changes in all thymic APCs in IFNaR/IFNlR deficient mice, and a loss of CCR7+ cDC1 cells. Together, these results show that steady state IFN-I and IFN-III signaling drives a gene-expression program in thymic APCs that shapes the thymic microenvironment. Bulk RNA-seq of thymocytes in WT, IFNAR1-KO, IFNB-KO, IFNAR1-KO IFNLR-KO, STAT1-KO, and IFNLR-KO mice.