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C-Maf is an essential commitment factor for IL-17-producing gd T cells [RNA-seq]

ABSTRACT: IL-17-producing gd T (Tgd17) cells are early mediators of immunity and autoimmunity that undergo effector programming in the thymus. While Vg subset-restricted regulators of Tgd17 specialization are known, a universal type 17 commitment factor for all gd T cells remains undefined. In this study, we identify the transcription factor c-Maf as an essential and uniform regulator of Tgd17 differentiation and maintenance. The absolute lineage block caused by Maf deficiency reveals a critical effector acquisition checkpoint at the immature CD24+ CD45RBlo gd thymocyte stage. Here, c-Maf enforces Tgd17 identity by promoting chromatin accessibility and activating expression of lineage-defining RORgt and key type 17 program genes, while coordinately antagonizing the negative regulator TCF1, which promotes the alternative IFNg+ Tgd1 fate. During specialization, c-Maf expression is tuned by gdTCR signal strength, implicating c-Maf as a rheostat controlling effector gd T cell generation and connecting gdTCR signals to a core node in the Tgd17 network.

ORGANISM(S): Mus musculus

PROVIDER: GSE120425 | GEO | 2018/12/03

REPOSITORIES: GEO

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c-Maf is an essential commitment factor for IL-17-producing gd T cells [ATAC-seq]

Project description:IL-17-producing gd T (Tgd17) cells are early mediators of immunity and autoimmunity that undergo effector programming in the thymus. While Vg subset-restricted regulators of Tgd17 specialization are known, a universal type 17 commitment factor for all gd T cells remains undefined. In this study, we identify the transcription factor c-Maf as an essential and uniform regulator of Tgd17 differentiation and maintenance. The absolute lineage block caused by Maf deficiency reveals a critical effector acquisition checkpoint at the immature CD24+ CD45RBlo gd thymocyte stage. Here, c-Maf enforces Tgd17 identity by promoting chromatin accessibility and activating expression of lineage-defining RORgt and key type 17 program genes, while coordinately antagonizing the negative regulator TCF1, which promotes the alternative IFNg+ Tgd1 fate. During specialization, c-Maf expression is tuned by gdTCR signal strength, implicating c-Maf as a rheostat controlling effector gd T cell generation and connecting gdTCR signals to a core node in the Tgd17 network.

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Genomic profiling of chromatin accessibility in gd T cells during thymic development

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Project description:Innate-like gd T effector subsets are exported from the thymus as “memory-like” cells prewired for rapid, specialized function. Previously, we showed that emergent gd subsets distinguished by TCRg and TCRd usage in the fetal and adult thymus possess distinct global transcriptomes and the subset-specific combinatorial expression of High Mobility Group box transcription factors (HMG TFs) shown as a primary determinant of gd effector differentiation. While the detailed mechanism of HMG TFs cooperativity and counter-regulations are not fully understood, a key feature for IL-17 producing gd T effectors (Tgd17) is predicted to be context-dependent interactions between SOX13 and TCF1 that result in diversified target gene regulation. More SOX13 allow more TCF1 dockings on DNA. TCF1 chromatin occupancy in the Tgd17 gene cluster (V2 set) mimics when the amount of SOX13 is enhanced like the Sox13 transgenic system. Globally 75% of SOX13 binding is overlapped with TCF1 binding and V2 set-specifically 85% of SOX13 targets are overlapped with TCF1 targets. Mostly V2 sets are H3K4me3 (79%) and the genome wide analysis between TCF1 and SOX13 indicate cooperative and active SOX13-dependent-TCF1-modulations on V2 sets.

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Essential functions of the transcription factors TCF1 and SOX13 in gdT cell development (Sox13tg_Sox13lo)

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2018-11-01 | GSE74641 | GEO

Integration of epigenetic and transcriptional mechanisms governs functional commitment versus plasticity of gd T cell subsets

Project description:gd T cells are major innate sources of interleukin-17 (IL-17) and interferon-g (IFN-g), which are differentially produced by two thymically-derived subsets segregated on CD27 expression. However, the molecular mechanisms that program the functional differentiation of gd cells remain incompletely understood. Here we show that CD27+ gd cells are epigenetically committed to express Ifng but not Il17, whereas CD27- gd cells spontaneously make IL-17 but can be induced to produce IFN-g under specific inflammatory conditions. This M-bM-^@M-^\plasticM-bM-^@M-^] behavior of CD27- gd cells associates with permissive histone H3 marks at loci encoding Ifng and upstream M-bM-^@M-^\type 1M-bM-^@M-^] transcription factors. By contrast, Il17 and related M-bM-^@M-^\type 17M-bM-^@M-^] factors are epigenetically and transcriptionally active in CD27- but silenced in CD27+ gd cells. Hence, stable versus plastic behaviors of gd cell subsets are controlled by integrated epigenetic and transcriptional mechanisms that regulate the expression of M-bM-^@M-^\masterM-bM-^@M-^] transcription factors and effector cytokine genes. ChIP was carried out on FACS-sorted cells from pooled spleen/ lymph nodes. The following antibodies were used: anti-histone H3K4me2 (07-030, Millipore) and anti-histone H3k27me3 (07-449, Millipore). Between 105 - 106 cells were crosslinked with formaldehyde and nuclei were isolated and sonicated with a Sanyo Soniprep 150 at an amplitude of 10 microns with 17 times 10s bursts, resulting in 200M-bM-^@M-^S400bp chromatin fragments. IP was carried out as previously described 49. The Immunoprecipitated DNA released from crosslinked proteins was extracted with the QiaQuick kit (Qiagen) in accordance with the manufacturerM-BM-4s instructions. Deep sequencing was performed at the GeneCore facility of EMBL (http://www.genecore.embl.de/). At least 1 ng of immunoprecipitated DNA was used for library preparation according to the Illumina protocol.

2013-09-01 | E-GEOD-42098 | biostudies-arrayexpress

RNA Sequencing of Tgd17 progenitors

Project description:Tgd17 cells are critical immune effector cells that exit the thymus committed to peripheral IL-17 responses, but whether the development of cells into this lineage is pre-programmed or driven by instructive TCR signals is unresolved. Using newly generated reporter mice for a gene necessary for Tgd17 cell development, Sox13, we identified progenitor cells (known as DN1d cells) that expressed high levels of Sox13 prior to expression of the TCR. To interrogate whether DN1d cells could be a candidate Tgd17-biased progenitor, whole transcriptome RNA sequencing was performed on these progenitors as well as canonical T cell progenitors thought to generate all T cell subsets and the proposed progeny Tgd17 cells. The data demonstrated that DN1d cells most closely resemble Tgd17 cells at a transcriptome level, while canonical T cell progenitors were very different from both DN1d cells and Tgd17 cells. Further studies demonstrated that DN1d cells generated Tgd17 cells in developmental assays, and that the transcriptional signature of DN1d cells is established and maintained independently of TCR expression or signaling but is instead dependent on HMG transcription factors SOX13 and TCF1. Thus, T cell lineage identity can be pre-programmed at the progenitor level and is not necessarily specified by specific TCR signals.

2018-08-23 | GSE118924 | GEO

c-Maf is an essential commitment factor for IL-17-producing gd T cells

Project description:c-Maf is an essential commitment factor for IL-17-producing gd T cells

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PBS vs. LPS stimulation of gd T cells

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