Thymic dendritic cell-derived IL-27p28 promotes the establishment of functional bias against IFN-γ production in newly generated CD4+T cells through STAT1-related epigenetic mechanisms

Abstract

AbstractThe newly generated CD4 single-positive (SP) T lymphocytes are featured by enhanced IL-4 but repressed IFN-γ production. The mechanisms underlying this functional bias remain elusive. Previous studies have reported that CD4+T cells from mice harboring DC-specific deletion of IL-27p28 display an increased capacity of IFN-γ production upon TCR stimulation. Here we demonstrated that similarly altered functionality occurred in CD4SP thymocytes, recent thymic emigrants (RTEs) as well as naive T cells from eitherCd11c-p28f/fmice or mice deficient in the α subunit of IL-27 receptor. Therefore, DC-derived IL-27p28-triggered, IL-27Rα-mediated signal is critically involved in the establishment of functional bias against IFN-γ production during their development in the thymus. Epigenetic analyses indicated reduced DNA methylation of theIfnglocus and increased trimethylation of H3K4 at bothIfngandTbx21loci in CD4SP thymcoytes fromCd11c-p28f/fmice. Transcriptome profiling demonstrated thatIl27p28ablation resulted in coordinated up-regulation of STAT1-activated genes. Concurrently, STAT1 was found to be constitutively activated. Moreover, we observed increased accumulation of STAT1 at theIfngandTbx21loci and a strong correlation between STAT1 binding and H3K4me3 modification of these loci. Of note,Il27p28deficiency exacerbated the autoimmune phenotype ofAire-/-mice. Collectively, this study reveals a novel mechanism underlying the functional bias of newly generated CD4+T cells and the potential relevance of such a bias in autoimmunity.Graphic abstract