HDAC1 restricts fungal-induced Th17 polarization to restrain tissue damage
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ABSTRACT:
PROVIDER: PRJNA1134136 | ENA |
REPOSITORIES: ENA
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Project description:Epigenetic mechanisms contribute to shaping many aspects of adaptive immunity, including T cell lineage functions in anti-infective surveillance. Histone deacetylases (HDAC) control T cell polarization but a role in fungal-specific T cell responses remains poorly understood. Here we show that CD4+ T cells are an integral part of the adaptive immune defense against invasive fungal infections. Temporally-resolved in vivo transcriptional profiles of splenic Th cells from infected mice harboring a CD4+-specific ablation of HDAC1 reveals its critical role in limiting T cell polarization towards Th17 at the expense of Th1-lineage commitment. Mechanistically, HDAC1 restricts expression of the cytokine receptors gp130 and TGFbRII on the T cell surface thus limiting Stat3 and Smad2/3 signaling in a fungal-specific manner. Controlled release of Th17-associated cytokines IL-17A and GM-CSF is vital to minimize epithelial apoptotic processes in renal tubular epithelial cells (RTECs) in vitro as well as during systemic infections in vivo. Consequently, protecting the host from excessive organ pathology, loss of kidney functionality and limiting fungal burdens, thus reducing sepsis-induced death during fungal infections. Collectively, this work shows that HDAC1 controls T cell lineage polarization, thus playing a critical role in the antifungal immune defense and infection outcome.
2024-12-05 | GSE271923 | GEO
Project description:HDAC1 restricts fungal-induced Th17 polarization to restrain tissue damage [Kidney RNA-seq]
| PRJNA1134751 | ENA
Project description:Epigenetic mechanisms contribute to shaping many aspects of adaptive immunity, including T cell lineage functions in anti-infective surveillance. Histone deacetylases (HDAC) control T cell polarization but a role in fungal-specific T cell responses remains poorly understood. Here we show that CD4+ T cells are an integral part of the adaptive immune defense against invasive fungal infections. Temporally-resolved in vivo transcriptional profiles of splenic Th cells from infected mice harboring a CD4+-specific ablation of HDAC1 reveals its critical role in limiting T cell polarization towards Th17 at the expense of Th1-lineage commitment. Mechanistically, HDAC1 restricts expression of the cytokine receptors gp130 and TGFbRII on the T cell surface thus limiting Stat3 and Smad2/3 signaling in a fungal-specific manner. Controlled release of Th17-associated cytokines IL-17A and GM-CSF is vital to minimize epithelial apoptotic processes in renal tubular epithelial cells (RTECs) in vitro as well as during systemic infections in vivo. Consequently, protecting the host from excessive organ pathology, loss of kidney functionality and limiting fungal burdens, thus reducing sepsis-induced death during fungal infections. Collectively, this work shows that HDAC1 controls T cell lineage polarization, thus playing a critical role in the antifungal immune defense and infection outcome.
2024-08-01 | GSE272036 | GEO
Project description:Analysis of Th17 polarization under different oxygen concentrations and environmental toxin exposure at gene expression level. Results provide important information of the response of CD4+ T cells to low oxygen , such as genes involved in metabolism, transcriptional factor, up- or down-regulated specific cellular functions.
2017-06-01 | GSE90882 | GEO
Project description:IL-10 production by Th17 cells is critical for limiting autoimmunity and inflammatory responses. Gene array analysis on Stat6 and T-bet double deficient Th17 cells identified the Th2 transcription factor c-Maf to be synergistically up-regulated by IL-6 plus TGFbeta, and associated with Th17 IL-10 production. Both c-Maf and IL-10 induction during Th17 polarization depended on Stat3, but not Stat6 or Stat1, and mechanistically differed from IL-10 regulation by Th2 or IL-27 signals. TGFbeta was also synergistic with IL-27 to induce c-Maf, and induced Stat1 independent IL-10 expression in contrast to IL-27 alone. Retroviral transduction of c-Maf was able to induce IL-10 expression in Stat6 deficient CD4 and CD8 T cells, and c-Maf directly transactivated IL-10 gene expression through binding to a MARE motif in the IL-10 promoter. Together, these data reveal a novel role for c-Maf in regulating T effector development, and suggest that TGFbeta may antagonize Th17 immunity by IL-10 production through c-Maf induction. Our recent studies showed that IL-6 combined with TGFbeta differed from IL-6 combined with IL-23 for IL-10 production and pathogenic activities in CD4 T cells deficient in Stat6 and T-bet, despite similar IL-17 production. We performed gene array analysis on Stat6 and T-bet double deficient cells. We rationalized that by comparing gene expression in cells treated with IL-6 plus TGFbeta versus TGFbeta alone, we would be able to identify genes specific for standard Th17 polarization, and responsible for both IL-17 and IL-10 expression. By next comparing gene expression in cells treated with IL-6 plus TGFbeta versus IL-6 plus IL-23, we could eliminate molecules involved solely in IL-17 regulation, and obtain genes specifically responsible for IL-10 regulation.
2009-03-03 | E-GEOD-15029 | biostudies-arrayexpress
Project description:IL-10 production by Th17 cells is critical for limiting autoimmunity and inflammatory responses. Gene array analysis on Stat6 and T-bet double deficient Th17 cells identified the Th2 transcription factor c-Maf to be synergistically up-regulated by IL-6 plus TGFbeta, and associated with Th17 IL-10 production. Both c-Maf and IL-10 induction during Th17 polarization depended on Stat3, but not Stat6 or Stat1, and mechanistically differed from IL-10 regulation by Th2 or IL-27 signals. TGFbeta was also synergistic with IL-27 to induce c-Maf, and induced Stat1 independent IL-10 expression in contrast to IL-27 alone. Retroviral transduction of c-Maf was able to induce IL-10 expression in Stat6 deficient CD4 and CD8 T cells, and c-Maf directly transactivated IL-10 gene expression through binding to a MARE motif in the IL-10 promoter. Together, these data reveal a novel role for c-Maf in regulating T effector development, and suggest that TGFbeta may antagonize Th17 immunity by IL-10 production through c-Maf induction.
2009-03-03 | GSE15029 | GEO
Project description:STAT3 is an immidiate regulator of Th17 differentiation. STAT3 difieciency downmodulate Th17 specific genes and Th17 responses. Therefore, we intend to identify genome wide targets of STAT3. We used microarrays to profile gene expression of STAT3 regulated genes during Th17 polarization. Total RNA was extracted from non-targeting and STAT3 siRNA treated Thp, Th0 and Th17 cell samples from different time points. Total RNA subjected to poly-A selection and hybridization on Affymetrix microarrays.
2017-05-03 | E-GEOD-67185 | biostudies-arrayexpress
Project description:We analyzed the genome wide distributions of HDAC1, HDAC4, HDAC7 in Th17 cells. We find that majority of HDAC4 and HDAC7 binding sites are HDAC1 bound. TMP269 inhibits HDAC4 and HDAC7 at promoter sites of Th17 negative regulator genes, leading to their upregulation through increased H3, H4 acetylation.
2018-12-16 | GSE92531 | GEO
Project description:The study aims at identifying transcriptional changes induced by in vitro polarization of human cord blood CD4+ cells towards Th17 subtype with combination of IL6, IL1b and TGFb by using timeseries data. In this study, we identified gene expression changes characterizing early stages of human Th17 cell differentiation program through genome-wide gene expression profiling. Primary T helper cells isolated from umbilical cord blood were used to construct detailed kinetic patterns of gene expression after initiation of Th17 differentiation with IL1b, IL6 and TGFb. The dataset described provides the starting point for defining the gene regulatory networks and identifying new candidates regulating the Th17 differentiation in human. Altogether 57 samples were analyzed representing 3 biological replicates of timeseries data (0, 0.5, 1, 2, 4, 6, 12, 24, 48 and 72 hours) of Th17 polarized cells and control Th0 cells
2012-05-03 | E-GEOD-35103 | biostudies-arrayexpress
Project description:Assessement of transcriptional consequences of CD27 signaling on Tregs during Th17 polarization
| PRJNA498509 | ENA