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TCR signaling induces STAT3 phosphorylation to promote TH17 cell differentiation

ABSTRACT: To systematically evaluate the effect of inhibition of Lck/Fyn kinase activity on the differentiation of TH17 and Treg cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE229377 | GEO | 2024/01/31

REPOSITORIES: GEO

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TCR signaling induces STAT3 phosphorylation to promote TH17 cell differentiation.

Project description:TH17 differentiation is critically controlled by "signal 3" of cytokines (IL-6/IL-23) through STAT3. However, cytokines alone induced only a moderate level of STAT3 phosphorylation. Surprisingly, TCR stimulation alone induced STAT3 phosphorylation through Lck/Fyn, and synergistically with IL-6/IL-23 induced robust and optimal STAT3 phosphorylation at Y705. Inhibition of Lck/Fyn kinase activity by Srci1 or disrupting the interaction between Lck/Fyn and STAT3 by disease-causing STAT3 mutations selectively impaired TCR stimulation, but not cytokine-induced STAT3 phosphorylation, which consequently abolished TH17 differentiation and converted them to FOXP3+ Treg cells. Srci1 administration or disrupting the interaction between Lck/Fyn and STAT3 significantly ameliorated TH17 cell-mediated EAE disease. These findings uncover an unexpected deterministic role of TCR signaling in fate determination between TH17 and Treg cells through Lck/Fyn-dependent phosphorylation of STAT3, which can be exploited to develop therapeutics selectively against TH17-related autoimmune diseases. Our study thus provides insight into how TCR signaling could integrate with cytokine signal to direct T cell differentiation.

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TCR signaling induces STAT3 phosphorylation to promote TH17 cell differentiation

Project description:TCR signaling induces STAT3 phosphorylation to promote TH17 cell differentiation

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Expression data from Th17 cells of different origins

Project description:Foxp3 is indispensable for Treg suppressive function, but the stability of Foxp3 has been controversial. In autoimmune arthritis, Th17 cells play a critically important pathological role, but the origin of Th17 cells remains unknown We used microarrays to detail the global programme of gene expression of Th17 cells originated from Foxp3+T cells compared to conventional naive CD4+T cells derived Th17 cells. We also take samples of Treg cells and Th0 cells for the experimetnatl control. Each T cell subset after the culture was subjected to RNA extraction and hybridization on Affymetrix microarrays.

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The effect of dexmedetomidine on perioperative cholinergic anti-inflammatory pathway and the balance of Th17 / Treg in colorectal cancer patients

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Project description:Oxidized low-density lipoprotein influences the Th17/Treg balance. A high serum concentration of oxidized low-density lipoprotein is negatively correlated with the number of Treg cells and positively correlated with the number of Th17 cells. Therefore, we expected that the reduction of blood lipid levels using ezetimibe and statin would ameliorate AS disease by reducing the number of Th17 cells.

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Expression data from Th17 cells of different origins

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Itaconate regulates Th17/Treg cell balance via metabolic and epigenetic reprogramming

Project description:An imbalance of T helper (Th17) cells and regulatory T (Treg) cells contributes to the pathogenesis of autoimmune diseases. The endogenous metabolite itaconate (ITA) is a regulator of macrophages; however, its role in T cells regulation is unclear. Here, we show that ITA inhibited Th17 cell differentiation and promoted Treg cell differentiation via metabolic and epigenetic reprogramming. Mechanistically, ITA suppressed glycolysis and mitochondrial respiration in Th17 and Treg-polarizing T cells. In Th17 cells, the S-adenosyl-L-methionine/ S-adenosylhomocysteine ratio was decreased following ITA administration in vitro, subsequently altering the epigenetic status. Further, ITA inhibited RORγt binding at the Il17a promoter, resulting in reduced IL-17A expression. In Treg cells, ITA reduced 2-hydroxyglutarate levels, which suppressed Foxp3 expression. The adoptive transfer of ITA-treated Th17-polarizing T cells ameliorated experimental autoimmune encephalomyelitis. Collectively, these results indicate that ITA serves as a crucial metabolic regulator for Th17/Treg cell balance and a potential therapeutic agent against autoimmune diseases.

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