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

The 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 dendritic cell (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 either <i>Cd11c-p28^f/f</i> mice 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 the <i>Ifng</i> locus and increased trimethylation of H3K4 at both <i>Ifng</i> and <i>Tbx21</i> loci in CD4SP thymocytes from <i>Cd11c-p28^f/f</i> mice. Transcriptome profiling demonstrated that <i>Il27p28</i> ablation resulted in the coordinated up-regulation of STAT1-activated genes. Concurrently, STAT1 was found to be constitutively activated. Moreover, we observed increased accumulation of STAT1 at the <i>Ifng</i> and <i>Tbx21</i> loci and a strong correlation between STAT1 binding and H3K4me3 modification of these loci. Of note, <i>Il27p28</i> deficiency exacerbated the autoimmune phenotype of <i>Aire^-/-</i> 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.