Th17 polarization under hypoxia
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE90882 | GEO | 2017/06/01
SECONDARY ACCESSION(S): PRJNA356274
REPOSITORIES: GEO
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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.
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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.
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