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Genome-wide analysis identifies Nr4a1 as a key mediator of T cell tolerance (ChIP-seq)

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE132476 | GEO | 2019/06/10

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.

2019-06-10 | GSE132477 | GEO

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

Project description: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.

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Personalized Neoantigen Cancer Vaccine in Glioblastoma Multiforme

Project description:<p>Neoantigens, which are derived from tumour-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses and can function as bona fide antigens that facilitate tumour rejection. We demonstrated that a strategy that uses multi-epitope, personalized neoantigen vaccination, which has previously been tested in patients with high-risk melanoma, is feasible for tumours such as glioblastoma, which typically have a relatively low mutation load and an immunologically ‘cold’ tumour microenvironment. Here we conducted whole-exome sequencing of tumor and normal cells from individual patients with glioblastoma to identify tumor-specific mutations. We assessed the expression of mutated alleles by RNA-sequencing of tumor. We used personalized neoantigen-targeting vaccines to immunize patients newly diagnosed with glioblastoma following surgical resection and conventional radiotherapy in a phase I/Ib study. Patients who did not receive dexamethasone-a highly potent corticosteroid that is frequently prescribed to treat cerebral oedema in patients with glioblastoma-generated circulating polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses that were enriched in a memory phenotype and showed an increase in the number of tumour-infiltrating T cells. Using single-cell T cell receptor analysis, we provide evidence that neoantigen-specific T cells from the peripheral blood can migrate into an intracranial glioblastoma tumour. Neoantigen-targeting vaccines thus have the potential to favourably alter the immune milieu of glioblastoma.</p>

| phs001519 | dbGaP

NR4A1 transcriptionally regulates the differentiation of stem-like CD8+ T cells in the tumor microenvironment (RNA-Seq)

Project description:CD8+ T cells are rendered exhausted in tumor and chronic infection. Among heterogeneous exhausted T cells, a subpopulation of progenitor-like (Tpex) cells have been found important for long-term tumor or pathogen control, and are also the main responders in immunotherapy. Using a new reporter mouse for the orphan nuclear receptor NR4A1, originally characterized critical in T cell dysfunction, we discover that the reporter is highly expressed in Tpex cells in tumor and chronic infection. Enforced expression of Nr4a1 promotes Tpex cell accumulation, whereas tumor control is improved after Nr4a1 deletion, associated with increased effector function but decreased long-term maintenance of CD8+ T cells. Integrating ChIP-seq and RNA-seq analysis, NR4A1 is found to bind and promote the expression of Tpex-related genes, and suppresses terminal differentiation-associated genes. This study therefore has identified a key role of NR4A1 in Tpex regulation and provides a promising target for immunotherapy.

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NR4A1 transcriptionally regulates the differentiation of stem-like CD8+ T cells in the tumor microenvironment (ChIP-Seq)

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BATF and IRF4 cooperate to counter exhaustion in tumour-infiltrating CAR T cells (RNA-seq)

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2021-07-13 | GSE154745 | GEO

BATF and IRF4 cooperate to counter exhaustion in tumour-infiltrating CAR T cells (ChIP-seq)

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BATF and IRF4 cooperate to counter exhaustion in tumour-infiltrating CAR T cells (ATAC-seq)

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Intragraft memory-like CD127hiCD4+Foxp3+ regulatory T cells maintain transplant tolerance

Project description:CD4+Foxp3+ regulatory T cells (Tregs) play an essential role in suppressing transplant rejection but their role within the graft, is poorly understood. To address this, we compared phenotypic and transcriptomic characteristics of Treg populations within lymphoid-organs and grafts in an islet xenotransplant model of tolerance induced by co-stimulation blockade. In this study, Tregs were essential for tolerance induction and their numbers increased over time. Tregs demonstrated phenotypic and transcriptional heterogeneity within the graft, and lymphoid organs of tolerant mice. A sub-population of CD127highTreg with memory-like and suppressive features were present in high proportions within long surviving islet-grafts of tolerant mice and had a transcriptomic profile consistent with tissue-Tregs. Importantly these CD127highTregs were better able to prevent rejection by effector T cells, after adoptive transfer into secondary Rag-/- hosts, than naïve Tregs, or unselected Tregs isolated from tolerant mice. We propose that after initial development within the draining lymph node they undergo further genetic reprogramming within the graft towards a phenotype that has shared characteristics with other tissue or tumour Tregs. These findings provide a new focus for engineering such cells either in vivo or for adoptive transfer for inducing tolerance.

2024-03-22 | GSE220447 | GEO

Gene expression profiling in B lymphocytes from transplanted patients

Project description:The achievement of a drug-free operational tolerance for renal transplanted patients is a major goal in organ transplantation. Previous gene expression profiling in peripheral blood mononuclear cells (PBMC) identified genes associated with operational tolerance. The identification of a common pattern of B cell-related genes associated with tolerance encourage us to analyze gene expression in purified B cell from operationally tolerant patients (TOL=10) compared to renal transplanted patients with stable graft function (STA=12) under immunosuppression and also compared to healthy volunteers (HV=10) who have no immunosuppressive treatment and no graft. Microarray analyses exhibited an absence of gene signature associated with tolerance in purified B cell compared to STA or HV. These results suggest that the B cell signatures observed in PBMC may be due to an increase number of total B cells rather than specific B cell characteristics in operationally tolerant patients. This dataset represents gene expression profiling of purified B cells from 10 renal transplanted patients with operational tolerance (TOL), 12 renal transplanted patients with stable graft function under immunosuppression (STA) and 10 healthy volunteers (HV).

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