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Early programming of CD8+ T cell response by the orphan nuclear receptor NR4A3 [RNA-Seq]

ABSTRACT: We analysed the transcriptomic gene signature of day 3 CD8+ T cell effectors in the absence of NR4A3 to determine the impact of this transcription factor on early transcriptomic programming of CD8 T cell memory and function

ORGANISM(S): Mus musculus

PROVIDER: GSE143512 | GEO | 2020/08/24

REPOSITORIES: GEO

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Early programming of CD8+ T cell response by the orphan nuclear receptor NR4A3 [ATAC-Seq]

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Early programming of CD8+ T cell response by the orphan nuclear receptor NR4A3

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Early programming of CD8+ T cell response by the orphan nuclear receptor NR4A3 [RNA-Seq]

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The orphan nuclear receptor NR4A3 is involved in the function of dendritic cells

Project description:Transcriptome analysis of LPS-stimulated bone marrow-derived dendritic cells with NR4A3 gene silencing The NR4A3/NOR1 belongs to the NR4A subfamily of the orphan nuclear hormone receptor superfamily, which is activated in a ligand-independent manner. To examine the role of NR4A3/NOR1 in gene expression of dendritic cells (DCs), we introduced NR4A3 siRNA into bone marrow-derived DCs (BMDCs) and determined the expression levels of mRNA and proteins of cytokines, cell surface molecules, NFκB signaling-related proteins, and transcription factors. The expression level of NR4A3 was markedly up-regulated by TLRs-mediated stimulation in DCs. NR4A3 knockdown significantly suppressed LPS, CpG, or poly I:C-mediated up-regulation of CD80, CD86, IL-10, IL-6, and IL-12. Proliferation and IL-2 production levels of T cells co-cultured with NR4A3-knocked down DCs were significantly lower than that of T cells co-cultured with control DCs. Furthermore, the expression of IKKβ, IRF4, and IRF8 was significantly decreased in NR4A3 siRNA-introduced BMDCs. The knockdown experiments using siRNAs for IKKβ, IRF4, and/or IRF8 indicated that LPS-induced up-regulation of IL-10 and IL-6 was reduced in IKKβ knocked down cells, and that the up-regulation of IL-12 was suppressed by the knockdown of IRF4 and IRF8. Taken together, these results indicate that NR4A3 is involved in TLR-mediated activation and gene expression of DCs.

2017-10-01 | GSE101831 | GEO

Early programming of CD8<sup>+</sup> T cell response by the orphan nuclear receptor NR4A3.

Project description:Enhancing long-term persistence while simultaneously potentiating the effector response of CD8+ T cells has been a long-standing goal in immunology to produce better vaccines and adoptive cell therapy products. NR4A3 is a transcription factor of the orphan nuclear receptor family. While it is rapidly and transiently expressed following T cell activation, its role in the early stages of T cell response is unknown. We show that NR4A3-deficient murine CD8+ T cells differentiate preferentially into memory precursor and central memory cells, but also produce more cytokines. This is explained by an early influence of NR4A3 deficiency on the memory transcriptional program and on accessibility of chromatin regions with motifs for bZIP transcription factors, which impacts the transcription of Fos/Jun target genes. Our results reveal a unique and early role for NR4A3 in programming CD8+ T cell differentiation and function. Manipulating NR4A3 activity may represent a promising strategy to improve vaccination and T cell therapy.

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Transcriptional profiling of monocytes deficient in Nuclear Orphan Receptors NR4A2 and NR4A3 reveals distinct signalling roles related to antigen presentation and viral response.

Project description:Using RNA-sequencing and strategic bioinformatic analysis we investigated the down-stream effects of NR4A2 and NR4A3 in monocytes and dissected their common and distinct signalling roles.NR4A2 selective genes were most associated with antigen presentation, NR4A3 selective genes were most associated with interferon/viral reponse and NR4A2/3 co-regulated genes were most associated with clasical innate immure response signaling e.g. TLR signaling and chemokine secretion.

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NR4A3 plays a pivotal role in the differentiation of monocyte-derived dendritic cells

Project description:The molecular requirements that guide the differentiation of monocytes into macrophages or monocyte-derived dendritic cells (Mo-DCs) are poorly understood. Here, we demonstrate that the nuclear orphan receptor NR4A3 guides monocyte fate and is essential for Mo-DC differentiation. Nr4a3-/- mice are impaired in the in vivo generation of DC-SIGN+ Mo-DCs following LPS stimulation and, as such, are defective at priming a CD8+ T cell response to gram negative bacteria. We also demonstrate that NR4A3 is an essential downstream effector of IRF4 during in vitro differentiation of Mo-DCs with GM-CSF and IL-4 and that, in absence of NR4A3, monocytes are diverted to macrophages. Our transcriptomic analysis of the genes regulated by NR4A3 reveals that the acquisition of the Mo-DC differentiation program is intertwined with the acquisition of a migratory signature. Furthermore, NR4A3 is critical for steady-state migration of non-lymphoid tissue conventional DCs to lymph nodes. Altogether, our results highlight a unique role for NR4A3 in Mo-DC differentiation and in the acquisition of migratory properties.

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Early programming of CD8+ T cell response by the orphan nuclear receptor NR4A3

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-08-24 | GSE143513 | GEO

BLIMP1 and NR4A3 Transcription Factors Reciprocally Regulate Antitumor CAR T-cell Stemness and Exhaustion [RNA-Seq]

Project description:Chimeric antigen receptor (CAR) T-cells have not induced meaningful clinical responses in solid tumor indications. Loss of T-cell stemness, poor expansion capacity and exhaustion during prolonged tumor antigen exposure are major causes of CAR T-cell therapeutic resistance. scRNA-sequencing analysis of CAR T-cells from a first-in-human trial in metastatic prostate cancer identified two distinct and independently validated cell states associated with antitumor potency or lack of efficacy. Low levels of the PRDM1 gene encoding the BLIMP1 transcription factor defined highly potent TCF7+CD8+ CAR T-cells, while enrichment of TIM3+CD8+ T-cells with elevated PRDM1 expression predicted poor outcome. PRDM1 single knockout promoted TCF7-dependent CAR T-cell stemness and proliferation resulting in marginally enhanced leukemia control. However, in the setting of PRDM1 deficiency, a negative epigenetic feedback program of NFAT-driven T-cell dysfunction characterized by compensatory upregulation of NR4A3 and multiple other genes encoding exhaustion-related transcription factors hampered effector function in solid tumors. PRDM1 and NR4A3 combined ablation skewed CAR T-cell phenotypes away from TIM3+CD8+ and toward TCF7+CD8+ to counter exhaustion of tumor-infiltrating CAR T-cells and improve in vivo antitumor responses, effects that were not achieved with BLIMP1 or NR4A3 single disruption alone. These data reveal a novel molecular targeting strategy to enrich stem-like CAR T-cells resistant to exhaustion and underscore dual inhibition of PRDM1/NR4A3 expression or activity as a promising approach to advance adoptive cell immuno-oncotherapy.

2022-08-04 | GSE210264 | GEO

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