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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE96969 | GEO | 2018/03/24

REPOSITORIES: GEO

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

Project description: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.

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