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Transcriptional and epigenetic regulation of adaptive NK cell responses [ChIP-Seq]

ABSTRACT: Natural killer (NK) cells are innate lymphocytes that possess features of adaptive immunity such as clonal expansion and generation of long-lived memory. Interleukin (IL)-12 signaling through its downstream transcription factor STAT4 is required for the generation of memory NK cells following expansion, while type I interferon through STAT1 is important for NK cell expansion. Here, we identify gene loci that are highly enriched for STAT4 binding using ChIP-seq for STAT4 and the permissive histone mark H3K4me3 in activated NK cells. In addition, we identify gene loci that are high enriched for STAT1 binding in response to type I interferon signaling.

ORGANISM(S): Mus musculus

PROVIDER: GSE106137 | GEO | 2017/12/20

SECONDARY ACCESSION(S): PRJNA415720

REPOSITORIES: GEO

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Transcriptional regulation of adaptive NK and CD8 T cell responses [RNA-Seq]

Project description:Natural killer (NK) cells are innate lymphocytes that possess features of adaptive immunity such as clonal expansion and generation of long-lived memory. Here we look at transcriptional profiles of NK cells throughout several time points during MCMV infection, ex-vivo cytokine stimulation, and/or deficiency of key transcription factors such as STAT4, STAT1, and Runx1. In addition, we profile parallel time points of MCMV-specific CD8 T cells during infection and memory formation.

2017-12-20 | GSE106138 | GEO

Divergent role for STAT5 in the adaptive responses of natural killer cells

Project description:Natural killer (NK) cells are innate lymphocytes with the capacity to elicit adaptive features, including clonal expansion and immunological memory. Because signal transducer and activator of transcription 5 (STAT5) is essential for NK cell development, the role of this transcription factor and its upstream cytokines IL-2 and IL-15 during infection have not been carefully investigated. In this study, we investigate how STAT5 regulates transcription during viral infection. We demonstrate that STAT5 is induced in NK cells by IL-12 and STAT4 early after infection, and that partial STAT5 deficiency results in a defective capacity of NK cells to generate long-lived memory cells. Furthermore, we find a functional dichotomy of IL-2 and IL-15 signaling outputs during viral infection, whereby both cytokines drive clonal expansion, but only IL-15 is required for memory NK cell survival. We thus highlight a novel role for STAT5 signaling in promoting an optimal antiviral NK cell response.

2020-12-27 | GSE142821 | GEO

Regulating type 1 IFN effects in CD8 T cells during viral infections: changing STAT4 and STAT1 expression for function

Project description:Type 1 IFNs can conditionally activate all of the signal transducers and activators of transcription molecules (STATs), including STAT4. The best-characterized signaling pathways use STAT1, however, and type 1 IFN inhibition of cell proliferation is STAT1 dependent. We report that type 1 IFNs can basally stimulate STAT1- and STAT4- dependent effects in CD8 T cells, but that CD8 T cells responding to infections of mice with lymphocytic choriomenigitis virus have elevated STAT4 and lower STAT1 expression with significant consequences for modifying the effects of type 1 IFN exposure. The phenotype was associated with preferential type 1 IFN activation of STAT4 as compared to STAT1. Stimulation through the TCR induced elevated STAT4 expression, and STAT4 was required for peak expansion of antigen-specific CD8 T cells, low STAT1 levels, and resistance to type 1 IFN-mediated inhibition of proliferation. Thus, a mechanism is discovered for regulating the consequences of type 1 IFN exposure in CD8 T cells, with STAT4 acting as a key molecule in driving optimal antigen-specific responses and overcoming STAT1-dependent inhibition of proliferation. CD8 T cells were purified from uninfected WT, STAT1-deficient and STAT4-deficient mice or from D8 LCMV-infected WT mice and either control treated or treated with 1x104 U mouse IFNalpha for 90 minutes.

2012-09-07 | E-GEOD-40666 | biostudies-arrayexpress

Epigenetic control of innate and adaptive immune memory [ATAC-Seq]

Project description:Clonal expansion and immunological memory are hallmark features of the mammalian adaptive immune response and essential for prolonged host control of pathogens. Recent work demonstrated that natural killer (NK) cells of the innate immune system also exhibit these adaptive traits during infection. Here we demonstrate that differentiating and ‘memory’ NK cells possess distinct chromatin accessibility states, and that their epigenetic profiles reveal a ‘poised’ regulatory program at the memory stage. Furthermore, we elucidate how individual STAT proteins differentially control epigenetic and transcriptional states early during infection. Finally, concurrent chromatin profiling of the canonical CD8+ T cell response against the same infection demonstrated parallel and distinct epigenetic signatures defining NK cells and CD8+ T cells. Overall, our study reveals the dynamic nature of epigenetic imprinting during the generation of innate and adaptive lymphocyte memory.

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Regulating type 1 IFN effects in CD8 T cells during viral infections: changing STAT4 and STAT1 expression for function

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STAT4 promotes Bhlhe40 induction to drive protective IFN-g from natural killer cells during viral infection [STAT4 CUT&RUN]

Project description:NK cells represent a cellular component of the mammalian innate immune system, and mount rapid responses against viral infection, including the secretion of the potent anti-viral effector cytokine IFN-g. Following mouse cytomegalovirus (MCMV) infection, Bhlhe40 was the most highly induced transcription factor in NK cells among the basic helix-loop-helix family. Bhlhe40 upregulation in NK cells depended upon IL-12 and IL-18 signals, with the promoter of Bhlhe40 enriched for STAT4 and the permissive histone H3K4me3, and STAT4-deficient NK cells showing an impairment of Bhlhe40 induction and diminished H3K4me3. Transcriptomic and protein analysis of Bhlhe40-deficient NK cells revealed a defect in IFN-g production during MCMV infection, resulting in diminished protective immunity following viral challenge. Finally, we provide evidence that Bhlhe40 directly promotes IFN-g by binding throughout the Ifng loci in activated NK cells. Thus, our study reveals how STAT4-mediated control of Bhlhe40 drives protective IFN-g secretion by NK cells during viral infection.

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STAT4 promotes Bhlhe40 induction to drive protective IFN-g from natural killer cells during viral infection [BHLHE40 CUT&RUN]

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STAT4 promotes Bhlhe40 induction to drive protective IFN-g from natural killer cells during viral infection [RNA-Seq]

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Divergent roles for STAT4 in shaping effector differentiation of ILC1 and NK cells during gut inflammation I

Project description:Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1) require the transcription factor STAT4 to elicit rapid effector responses and protect against pathogens. Herein, by combining genetic and transcriptomic approaches, we revealed that STAT4 played an unexpected divergent role in regulating effector differentiation of murine ILC1 and NK cells, during intestinal inflammation. Stat4 deletion in Ncr1-expressing cells led to an increased generation of cytotoxic ILC1 in the inflamed large intestine. By contrast, Stat4-deficient NK cells showed impaired terminal differentiation, characterized by lower levels of IRF-8 and KLRG1. STAT4 expression in NCR+ innate lymphocytes restrained gut inflammation and controlled both systemic IFN-g levels and the number of type 2 adaptive T cells in the large intestine. Collectively our data shed light on shared and distinctive mechanisms of transcriptional regulation driven by STAT4 in NK cells and ILC1 required for protection during intestinal inflammation.

2023-09-28 | GSE210483 | GEO

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