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

ABSTRACT: 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 “plastic” behavior of CD27- gd cells associates with permissive histone H3 marks at loci encoding Ifng and upstream “type 1” transcription factors. By contrast, Il17 and related “type 17” 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 “master” transcription factors and effector cytokine genes.

ORGANISM(S): Mus musculus

PROVIDER: GSE42098 | GEO | 2013/09/01

SECONDARY ACCESSION(S): PRJNA179131

REPOSITORIES: GEO

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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

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.

2018-12-03 | GSE120426 | GEO

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

2018-12-03 | GSE120425 | GEO

RNA-seq of sorted mouse gdT cell populations based on TCR Vg chain and Ly6C status

Project description:Gamma-delta (gd) T cells from pooled mouse lymph nodes and spleens were isolated and FACS-sorted for Vg1+Ly6C-, Vg1+Ly6C+, Vg4+Ly6C- and Vg4+Ly6C+ subsets of bulk CD27+ gdT cells.

2024-04-16 | E-MTAB-13897 | biostudies-arrayexpress

Transcriptome comparison between TCR γδ T subsets reveals their exclusive and shared markers

Project description:Intestinal intraepithelial gamma-delta T cells (iIEL gd T cells) constitute a peculiar subset of T lymphocytes located in the gut epithelial barrier involved in intestinal homeostasis. To date, type 1 and type 17 TCR gamma-delta T cells have been well characterized into two functional categories based on phenotypic and functional markers e.g. CD44 and CD27. However, It remains to be determined how to classify iIEL gamma T cells based on commonly used markers. We addressed this question by comparing the transcriptomes of mouse iIEL gamma-delta T cells with distinct functionally well-described gamma-delta T cells present in the periphery.

2022-06-29 | GSE198703 | GEO

Altered thymic differentiation and modulation of arthritis by invariant NKT cells expressing mutant ZAP70 [RNA-Seq]

Project description:Various subsets of invariant natural killer T (iNKT) cells with different cytokine productions develop in the mouse thymus, but the factors driving their differentiation remain unclear. Here we show that hypomorphic alleles of Zap70 or chemical inhibition of Zap70 catalysis lead to an increase of IFN-g-producing iNKT cells (NKT1 cells), suggesting NKT1 cells may require a lower TCR signal threshold. Zap70 mutant mice develop IL-17-dependent arthritis. iNKT cells and therapeutic induction of IFN-g secretion by activating iNKT cells are protective in this model, but the representation of IFNg versus IL-17 secreting iNKT cells in the joint change in favor of IL-17 producers as disease worsened. NKT1 cells are also present in the synovial fluid of arthritis patients, where they could be beneficial. Our data therefore suggest that TCR signal strength during thymic differentiation may influence not only IFNg production, but also the protective function of iNKT cells in arthritis.

2018-05-17 | GSE114555 | GEO

Altered thymic differentiation and modulation of arthritis by invariant NKT cells expressing mutant ZAP70 [II]

2018-05-18 | GSE114594 | GEO

Methylation profiling of mouse T cells reveals epigenetic mechanisms underlie t cell plasticity

Project description:Multipotential naïve CD4+ T cells differentiate into distinct lineages including T helper 1 (Th1), Th2, Th17, and inducible T regulatory (iTreg) cells. The remarkable diversity of CD4+ T cells begs the question whether the observed changes reflect terminal differentiation with heritable epigenetic modifications or plasticity in T cell responses. We generated genome-wide histone H3 lysine 4 (H3K4) and lysine 27 (H3K27) trimethylation maps in naïve, Th1, Th2, Th17, iTreg, and natural (n)Treg cells. We found that although modifications of signature cytokine genes (Ifng, Il4, and Il17) partially conform to the expectation of lineage commitment, critical transcription factors such as Tbx21 exhibit a broad spectrum of epigenetic states, consistent with our demonstration of T-bet and IFN-? induction in nTreg cells. Our data suggest an epigenetic mechanism underlying the specificity and plasticity of effector and regulatory T cells and also provide a framework for understanding complexity of CD4+ T helper cell differentiation. Experiment Overall Design: Different T helper subsets are profiled for mRNA expression.

2009-01-16 | E-GEOD-14308 | biostudies-arrayexpress

Global Mapping of Histone H3 K4 and K27 Trimethylation: Lineage Fate Determination of Differentiating CD4+ T Cells

Project description:Multipotential naïve CD4+ T cells differentiate into distinct lineages including Th1, Th2, Th17, and inducible T regulatory (iTreg) cells. The remarkable diversity of CD4+ T cells begs the question whether the observed changes reflect terminal differentiation with heritable epigenetic modifications or plasticity in T cell responses. We generated genome-wide histone H3 lysine 4 (H3K4) and lysine 27 (H3K27) trimethylation maps in naïve, Th1, Th2, Th17, iTreg, and natural (n)Treg cells. We find that while modifications of signature cytokine genes (Ifng, Il4, and Il17) partially conform to the expectation of lineage commitment, critical transcription factors such as Tbx21 exhibit a broad spectrum of epigenetic states, consistent with our demonstration of T-bet and IFN-γ induction in nTreg cells. Our data suggest an epigenetic mechanism underlying the specificity and plasticity of effector and regulatory T cells and also provide a framework for understanding complexity of CD4+ T helper cell differentiation. genome-wide analysis of histone H3 K4 and K27 trimethylation in different sub-lineages of mouse CD4+ T cells. (12 samples in total)

2009-01-21 | E-GEOD-14254 | biostudies-arrayexpress

Transient expression of T-bet epigenetically imprints the Ifng locus for its expression in a distinct Tfh cell subset

Project description:T follicular helper (Tfh) cells, which reside in the B cell follicles and help Ig class switching, express the master transcription factor BCL-6 and signature cytokine IL-21. Tfh cells are also capable of expressing IFN-g, however, whether IFN-g-producing Tfh population represents a unique Tfh subset and how they develop are unknown. While T-bet is the master regulator for IFN-g production in Th1 cells, Tfh cells express no or very low levels of T-bet. Here, by using a T-bet-fate-mapping mouse strain, we report that all the IFN-g-producing Tfh cells identified after immunization have previously expressed T-bet. DNase I hypersensitivity analysis indicates that the Ifng gene locus is partially accessible in this ‘ex-T-bet’ population but inaccessible in Tfh cells without a history of T-bet expression. Furthermore, multi-color tissue imaging shows that some “ex-T-bet” Tfh cells reside in germinal centers and express IFN-gin situ. Finally, IFN-g-expressing Tfh cells are absent in T-bet-deficient mice and the Ifng gene is inaccessible in T-bet-deficient Tfh cells. Thus, transient expression of T-bet epigenetically imprints the Ifng locus for cytokine production in Tfh cells. Our results also indicate that Tfh cells are composed of different subsets and they may use genetic programs similar to those of classical non-Tfh T helper cells in order to acquire unique cytokine producing capacity.RNA-Seq analysis of gene expression in splenic CD4+CD44highCD25- T cell subsets. RNA-Seq analysis of gene expression in antigen-specific Tfh cells and non-Tfh cells that have a history of T-bet expression. DNase 1-Seq of T-bet expressed and un-expressed Tfh cells and non-Tfh cells.

2018-09-17 | GSE102959 | GEO

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