CD28 co-stimulatory signaling and AP-1 transcription factor are involved in the establishment of open chromatin during T cell activation.

Abstract

Abstract Upon encountering an antigen, naïve T helper (Th) cells are activated, differentiate into several lineages and contribute to immune response. Epigenetic changes at several cytokine and other effector genes during activation has been described previously, but the mechanism behind these changes is not understood. Here, we have profiled open chromatin during human T cell activation using ATAC-Seq approach and identified the regions where epigenetic changes take place genome-wide. Open chromatin formation correlated with induction of gene expression at nearby genes. This gene set was also enriched for functions related to T cell activation and immune response in GO analysis. T cell activation requires antigen signaling via T cell receptor and co-stimulation via CD28 which in turn result in nuclear translocation of NFAT and AP-1 transcription factors. For this reason, we profiled genome-wide distribution of these proteins during activation by ChIP-Seq. Our results show that 73% of activation-induced open chromatin loci contain binding sites for AP-1, whereas 39% of them bind NFAT. Over 90 % of the binding sites for NFAT were shared with AP-1 binding sites. We and others have previously shown that the lack of co-stimulation results in reduction or delay of AP-1 translocation into the nucleus. In order to confirm the role of AP-1 in establishment of the open chromatin structure during activation we mapped open chromatin in the cells that were activated without co-stimulation. Our data showed that ATAC signal was reduced at the open chromatin sites bound by AP-1 in the absence of co-stimulation, suggesting that CD28 signaling and AP-1 transcription factor are involved in open chromatin formation during T cell activation.