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IL-27 driven transcriptional network identifies regulators of IL-10 expression across T helper cell subsets[Prdm1/Maf KO Tr1 ATAC-seq]

ABSTRACT: IL-27 driven transcriptional network identifies regulators of IL-10 expression across T helper cell subsets[Prdm1/Maf KO Tr1 ATAC-seq]

PROVIDER: PRJNA666212 | ENA |

REPOSITORIES: ENA

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IL-27 driven transcriptional network identifies regulators of IL-10 expression across T helper cell subsets[Prdm1/Maf KO Tr1 ATAC-seq]

Project description:IL-27 is an immunoregulatory cytokine that suppresses inflammation through multiple mechanisms including induction of IL-10, but the transcriptional network mediating its diverse functions remains unclear. Combining temporal RNA profiling with computational algorithms, we predict 79 transcription factors induced by IL-27 in T cells. We validate 11 known and discover 5 positive (Cebpb, Fosl2, Tbx21, Hlx, Atf3) and 2 negative (Irf9, Irf8) Il10 regulators, generating an experimentally refined regulatory network for Il10. We report two central regulators Prdm1 and Maf that cooperatively drive the expression of signature genes induced by IL-27 in Type 1 regulatory T cells, mediate IL-10 expression in all T helper cells, and determine the regulatory phenotype of colonic Foxp3+regulatory T cells. Prdm1/Maf double-knockout mice develop spontaneous colitis, phenocopying the ll10 deficient mice. Our work provides insights for IL-27 driven transcriptional networks and identifies two shared Il10 regulators that orchestrate immunoregulatory programs across T helper cell subsets.

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IL-27 driven transcriptional network identifies regulators of IL-10 expression across T helper cell subsets[Prdm1/Maf KO colonic CD4 T cells scRNA-seq]

Project description:IL-27 driven transcriptional network identifies regulators of IL-10 expression across T helper cell subsets[Prdm1/Maf KO colonic CD4 T cells scRNA-seq]

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IL-10 Receptor Signaling is essental for Tr1 cell function in vivo

Project description:Interleukin-10 (IL-10) is essential to maintain intestinal homeostasis. CD4+ T regulatory type 1 (TR1) cells produce large amounts of this cytokine and being therefore currently examined in clinical trials as T-cell therapy in patients with inflammatory bowel disease (IBD). However, factors and molecular signals sustaining TR1 cell regulatory activity still need to be identified in order to optimize the efficiency and to ensure the safety of these trials. We investigated the role of IL-10 signaling in mature TR1 cells in vivo. Double IL-10eGFP Foxp3mRFP reporter mice and transgenic mice with impairment in IL-10 receptor signaling were used to test the activity of TR1 cells in a murine IBD model, a model that resembles the trials performed in humans. The molecular signaling was elucidated in vitro. Finally, we used human TR1 cells, currently employed for cell therapy, to confirm our results. We found that murine TR1 cells expressed functional IL-10 receptor α. TR1 cells with impaired IL-10 receptor signaling lost their regulatory activity in vivo. TR1 cells required IL-10 receptor signaling in order to activate p38 MAP kinase, thereby sustaining IL-10 production, which ultimately mediated their suppressive activity. Finally, we confirmed these data using human TR1 cells. In conclusion TR1 cell regulatory activity is dependent on IL-10 receptor signaling. These data suggest that in order to optimize TR1 cell-based therapy, IL-10 receptor expression has to be taken into consideration.

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IL-27 driven transcriptional network identifies regulators of IL-10 expression across T helper cell subsets[Tr1 differentiation with IL-27 microarray]

Project description:IL-27 driven transcriptional network identifies regulators of IL-10 expression across T helper cell subsets[Tr1 differentiation with IL-27 microarray]

| PRJNA667947 | ENA

Prdm1

Project description:Prdm1

| PRJNA300302 | ENA

IL-27 driven transcriptional network identifies regulators of IL-10 expression across T helper cell subsets[Tr1 deficient in TFs RNA-seq]

Project description:IL-27 driven transcriptional network identifies regulators of IL-10 expression across T helper cell subsets[Tr1 deficient in TFs RNA-seq]

| PRJNA666419 | ENA

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