Integration of Phospho-Signaling and Transcriptomics in Single Cells Reveals Distinct Th17 Cell Fates
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PROVIDER: PRJNA1262469 | ENA |
REPOSITORIES: ENA
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Project description:T-helper 17 (Th17) cells play a dual role in immunological responses, serving as essential components in tissue homeostasis and host defense against microbial pathogens, while also contributing to proinflammatory conditions and autoimmunity. While Transforming Growth Factor-beta 1 (TGFβ1) is pivotal for the differentiation of non-pathogenic Th17 cells, the role of TGFβ3 and Activin in steering Th17 cells toward a pathogenic phenotype has been acknowledged. However, the molecular mechanisms governing this dichotomy remain elusive. In this study, we demonstrate that the transcription factor Foxo1 is upregulated in a TGFβ1 dose-dependent manner, serving as a critical regulator that specifically modulates the fate of pathogenic Th17 cells. Analyses in both uveitis patients and an Experimental Autoimmune Uveitis (EAU) mouse model reveal a strong correlation between disease severity and diminished Foxo1 expression levels. Ectopic expression of Foxo1 selectively attenuates IL-17A production under pathogenic Th17-inducing conditions. Moreover, enhanced Foxo1 expression, triggered by TGFβ1 signaling, is implicated in fatty acid metabolism pathways that favor non-pathogenic Th17 differentiation. Our drug screening identifies several FDA-approved compounds capable of upregulating Foxo1. Collectively, our findings offer compelling evidence that Foxo1 serves as a molecular switch to specifically control pathogenic versus non-pathogenic Th17 differentiation in a TGFβ1-dependent manner. These insights suggest that targeting Foxo1 could be a promising therapeutic strategy for autoimmune diseases, offering efficacy without compromising immune homeostasis.
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Project description:T helper 17 (Th17) cells are heterogeneous; homeostatic Th17 (Th17Hom) cells maintain tissue homeostasis and pro-inflammatory Th17 (Th17Inf) cells drive autoimmune inflammation. IL-23 drives Th17Inf, but the signals that maintain Th17Hom remain unclear. Here, we found that differential glucocorticoid (GC) production downstream of CYP11A1, a critical enzyme for steroidogenesis, distinguished Th17Hom cells from Th17Inf cells. Although TCR signaling opened the Cyp11a1 locus, TGFβ1 and IL-6, key cytokines for Th17Hom cell differentiation, maintained and amplified Cyp11a1. Th17Hom cell-derived GC signaled through the glucocorticoid receptor (GR), which was higher in Th17Hom cells compared to Th17Inf cells, thereby forming a circuit that maintained the homeostatic state. Integration of multi-omics data from CYP11A1- and GR-deficient Th17Hom cells revealed a gene network underlying this circuit. TGFβ1, a key node in the network, restored GC sensing to Th17Inf. We thus identify a GC signaling circuit that maintains Th17 homeostasis with implications for treating Th17-mediated autoimmunity.
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Project description:Genome-wide analysis of Jarid2, Suz12, and c-Maf binding and H3K27me3 profiling in miR-155 KO and WT Th17 performed by ChIP-seq. We found that Jarid2 and c-Maf is differentially expressed in absence of miR-155 and they compete for binding to the Il22 promoter. We highlight targets of Jarid2 and Suz12 in miR-155 KO Th17 cells that are epigenetically silenced by increased H3K27me3 status. Furthermore, genome-wide analysis through Suz12 ChIP-exo in WT and Jarid2fl/fl;CD4cre Th17 reveals defects in PRC2 recruitment in abscence of Jarid2 that results in derepression of genes in Th17 cells. Thus, one main function of miR-155 is to curb epigenetic silencing by targeting Jarid2. Examination of Jarid2, Suz12, c-Maf binding and H3K27me3 changes in miR-155 KO and WT Th17.
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