GSE135247
ChIP Seq of influenza specific primary, memory and secondary CD4+ T cells [InVitro]
Immune responses to infection involve a careful balance: too weak a response allows pathogen replication; too strong risks immunopathology. The immunoregulatory cytokine IL-10 is a key factor in this balance, but the impact of IL-10 is context-dependent and current understanding of the factors that regulate IL-10 is incomplete. In this study, we demonstrated that the infection induced cytokine IL-27 promotes IL-10 expression in CD4+ T cells by directing epigenetic changes in H3K4me3, H3K27me3, H3K4me1 and H3K27Ac modifications at the Il10 locus. We showed that primary activation of antigen-specific CD4+ T cells, in the context of murine influenza infection, led to the long-term remodelling of the epigenetic landscape at both the Il10 promoter and a distinct active enhancer element ~ 25 kb upstream of the TSS. Intact IL-27 signalling was an essential requirement for these persistent epigenetic changes in memory CD4+ Tcells. We identified CREB1 as a transcription factor binding the Il10 active enhancer, and we showed that the ability of IL-27 to promote IL-10 expression was dependent on the histone acetyl transferase activity of the CREB1 complex member, p300. Together our data provide mechanistic insight into the action of IL-27 in regulating an immune response. We suggest that infection-induced cytokine signals direct epigenetic changes that moderate cytokine output in response to T cell receptor stimulation, regulating immune activity at sites of infection. Overall design: 36 samples;  naïve VertX, naïve VertX TCCR, in vitro VertX, in vitro VertX TCCR