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Role of PIP5K1a in human Th17 gene expression

ABSTRACT: This data was performed as part of Revu et al, "Human IL-17A protein expression is controlled through a PIP5K1a-dependent ARS2 checkpoint". IL-17 secreted by TH17 cells is beneficial for microbial control, but causes inflammation and pathological tissue remodeling in autoimmunity. Hence TH17 differentiation and IL-17 production must be tightly regulated, but to date this has been defined only in terms of transcriptional control. Phosphatidyinositols are second messengers activated during T cell activation that transduce signals from the TCR and costimulatory receptors at the cell membrane. Here we show phosphatidylinositol(4,5)bisphosphate (PIP2) was unexpectedly enriched in the nucleus of human TH17 cells, dependent on the kinase PIP5K1, and that blockade of PIP5K1 impaired IL-17A production. In contrast, nuclear PIP2 enrichment was not observed in Th1 or Th2 cells and these subsets did not require PIP5K1 for cytokine production. In multiple sclerosis patient T cells, IL-17 production elicited by myelin basic protein could be inhibited by PIP5K1 blockade. Surprisingly, PIP5K1 blockade did not alter IL17A mRNA levels or stability in TH17 cells. Instead, analysis of PIP5K1-interacting proteins revealed that PIP5K1 targets ARS2, a nuclear cap binding complex scaffold protein, to facilitate ARS2 binding to IL17A mRNA and subsequent IL-17 protein expression, uncovering a new mechanism for regulating IL-17A protein production and suggesting a novel mechanism of translation control of cytokines.

ORGANISM(S): Homo sapiens

PROVIDER: GSE232436 | GEO | 2023/05/15

REPOSITORIES: GEO

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Enhanced Pathogenicity of Th17 cells Generated in the Absence of Transforming Growth Factor-β Signaling

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Project description:Important immune regulatory mechanisms mediated by CD4+ and CD8+ T-cells keep untoward CD4+ T-cell responses in check. CD4+ T-helper 17 (Th17) cells, characterized by IL-17 production, play critical roles in the body’s response to infections and cancer and in the pathogenesis of autoimmune diseases such as multiple sclerosis, psoriasis, arthritis, IBD, among others. Here we demonstrate that human CD4+ T-cells cells exposed to a Th17-differentiating milieu are highly resistant to immune suppression by CD8+ T-cells, compared to control Th0 cells. This resistance is mediated, in part, through the action of IL-17A, IL-17F and IL-17AF heterodimer through their receptors (IL-17RA and IL-17RC) on CD4+ T-cells themselves, but not through their action on CD8+ T-cells or APC. We further show that IL-17 can directly act on non-Th17 effector CD4+ T-cells to induce suppressive resistance and this resistance can be reversed by blockade of IL-1, IL-6 or STAT3. These studies reveal a novel function for IL-17 cytokines in a CD4-intrinsic mechanism of immune resistance. The pathways induced in this process may serve as a critical target for intensive investigation and therapeutic intervention.

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Project description:CD4+ T cells that selectively produce interleukin (IL)-17, are critical for host defense and autoimmunity. Crucial for T helper17 (Th17) cells in vivo, 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 specification. 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. Examination of Stat3 binding and H3K4me and H3Ac in helper T cells.

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2020-03-29 | GSE129028 | GEO

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