GSE132476
Genome-wide analysis identifies Nr4a1 as a key mediator of T cell tolerance (ChIP-seq)
T cells become dysfunctional when they encounter self antigens or are exposed to chronic infection or to the tumour microenvironment1. The function of T cells is tightly regulated by a combinational co-stimulatory signal, and dominance of negative co-stimulation results in T cell dysfunction2. However, the molecular mechanisms that underlie this dysfunction remain unclear. Here, using an in vitro T cell tolerance induction system in mice, we characterize genome-wide epigenetic and gene expression features in tolerant T cells, and show that they are distinct from effector and regulatory T cells. Notably, the transcription factor NR4A1 is stably expressed at high levels in tolerant T cells. Overexpression of NR4A1 inhibits effector T cell differentiation, whereas deletion of NR4A1 overcomes T cell tolerance and exaggerates effector function, as well as enhancing immunity against tumour and chronic virus. Mechanistically, NR4A1 is preferentially recruited to binding sites of the transcription factor AP-1, where it represses effector-gene expression by inhibiting AP-1 function. NR4A1 binding also promotes acetylation of histone 3 at lysine 27 (H3K27ac), leading to activation of tolerance-related genes. This study thus identifies NR4A1 as a key general regulator in the induction of T cell dysfunction, and a potential target for tumour immunotherapy. Overall design: 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.