Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction

The molecular mechanism underlying T cell tolerance remains unclear. Here we utilize an in vitro T cell tolerance induction system to characterize genome-wide epigenetic and gene expression features intolerant T cells, which reveals they are distinct from effector and regulatory T cells. Importantly, transcription factor Nr4a1 is stably expressed at high levels in tolerant T cell.Nr4a1 overexpression inhibits effector T cell differentiation, whereas deletion of Nr4a1 overcomes T cell tolerance, exaggerates effector function, and enhances immunity against tumor and virus. Mechanistically, Nr4a1 is preferentially recruited to AP-1 sites and inhibits the recruitment of c-Jun and BATF as a mechanism for effector gene repression. On the other hand, for activation of tolerance-related genes, Nr4a1 binding promotes acetylation of histone H3 at K27.This study thus identifies Nr4a1 as a key regulator in T cell tolerance, which may be targeted in tumor immunotherapy. Genome-wide examination of H3K4me3 and H3K27me3 histone modifications across in vitro-generated CD4+ T cell subsets including naive, Th1, Th2, Th17, nTreg, and tolerant T cell. Genome-wide examination of Nr4a1, C-Jun, and Batf bindings, as well as H3k27ac peaks across chromain in Nr4a1-overexpressed T cell, Naive T cell, TCR/co-stimulation-activated T cell, as well as Nr4a1-deficient T cells.