Antibody blockade of IL-17-family cytokines in immunity to acute murine oral mucosal candidiasis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Elaine Tritto
PROVIDER: E-MTAB-4167 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:We compared the methylated and non-methylated regions in the genome of ex vivo-isolated naive CD4+ T cells, Th1 cells, Th17 cells and regulatory T cells by methyl-CpG binding domain protein sequencing (MBD-seq). Naive T cells and Th1 cells share more methylated regions than naive T cells and Th17 cells or Th1 and Th17 cells. However, analysis of the non-methylated regions revealed the highest similarity between Th1 and Th17 cells. Another aim was the analysis of the Th17 lineage on the basis of the methylome. We searched for regions absent in the methylome of Th17 but present in naive T cells, Th1 cells and regulatory T cells. Here, we identified differential methylation in the loci of Il17a, Chn2, Dpp4 and Dclk1. CD4+ T effector cells were prepared ex vivo, stimulated with PMA/Ionomycin, subjected to a comercially available cytokine secretion kit (IL-17A and IFNg), stained by adding fluorescence-labeled antibodies against CD3, CD4 and CD45RB and sorted by flow cytometry. We sorted naive CD4+ T cells (CD3+CD4+CD45RB_high), Th1 cells (CD3+CD4+CD45RB_low_IFNg+IL17A-), Th17 cells (CD3+CD4+CD45RB_low_IFNg-IL17A+) and regulatory T cells (CD3+CD4+CD25++).
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Project description:CD4+ T cells that selectively produce interleukin (IL)-17, are critical for host defense and autoimmunity1-4. Crucial for T helper17 (Th17) cells in vivo5,6, IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been argued to be the factors responsible for initiating specification7-10. Herein, we show that Th17 differentiation occurs in the absence of TGF-β signaling. Neither IL-6 nor IL-23 alone efficiently generated Th17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naïve precursors, independently of TGF-β. Epigenetic modification of the Il17a/Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed Rorγt and T-bet. T-bet+Rorγt+ Th17 cells are generated in vivo during experimental allergic encephalomyelitis (EAE), and adoptively transferred Th17 cells generated with IL-23 in the absence of TGF-β1 were more pathogenic in this experimental disease. These data suggest a new model for Th17 differentiation. Consistent with genetic data linking the IL23R with autoimmunity, our findings re-emphasize the role of IL-23 and therefore have important implications for the development of new therapies. Mouse T helper 17 cell differentiation with or without TGFB
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Project description:Extensive cellular heterogeneity exists within specific immune-cell subtypes classified as a single lineage, but its molecular underpinnings are rarely characterized at a genomic scale. Here, we use single-cell RNA-seq to investigate the molecular mechanisms governing heterogeneity and pathogenicity of Th17 cells isolated from the central nervous system (CNS) and lymph nodes (LN) at the peak of autoimmune encephalomyelitis (EAE) or polarized in vitro under either pathogenic or non-pathogenic differentiation conditions. Computational analysis reveals a spectrum of cellular states in vivo, including a self-renewal state, Th1-like effector/memory states and a dysfunctional/senescent state. Relating these states to in vitro differentiated Th17 cells, unveils genes governing pathogenicity and disease susceptibility. Using knockout mice, we validate four novel genes: Gpr65, Plzp, Toso and Cd5l (in a companion paper). Cellular heterogeneity thus informs Th17 function in autoimmunity, and can identify targets for selective suppression of pathogenic Th17 cells while sparing non-pathogenic tissue-protective ones. Population transcriptional profiling of Th17 cells, isolated from the lamina propria of the large intestine from 3-6 month old IL-17GFP KI mice
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