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DUSP6 mediates T cell receptor-engaged glycolysis and restrains T_FH cell differentiation.

ABSTRACT: Activated T cells undergo metabolic reprogramming and effector-cell differentiation but the factors involved are unclear. Utilizing mice lacking DUSP6 (DUSP6^-/-), we show that this phosphatase regulates T cell receptor (TCR) signaling to influence follicular helper T (T_FH) cell differentiation and T cell metabolism. In vitro, DUSP6^-/- CD4⁺ T_FH cells produced elevated IL-21. In vivo, T_FH cells were increased in DUSP6^-/- mice and in transgenic OTII-DUSP6^-/- mice at steady state. After immunization, DUSP6^-/- and OTII-DUSP6^-/- mice generated more T_FH cells and produced more antigen-specific IgG2 than controls. Activated DUSP6^-/- T cells showed enhanced JNK and p38 phosphorylation but impaired glycolysis. JNK or p38 inhibitors significantly reduced IL-21 production but did not restore glycolysis. TCR-stimulated DUSP6^-/- T cells could not induce phosphofructokinase activity and relied on glucose-independent fueling of mitochondrial respiration. Upon CD28 costimulation, activated DUSP6^-/- T cells did not undergo the metabolic commitment to glycolysis pathway to maintain viability. Unexpectedly, inhibition of fatty acid oxidation drastically lowered IL-21 production in DUSP6^-/- T_FH cells. Our findings suggest that DUSP6 connects TCR signaling to activation-induced metabolic commitment toward glycolysis and restrains T_FH cell differentiation via inhibiting IL-21 production.

SUBMITTER: Hsu WC

PROVIDER: S-EPMC6112722 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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DUSP6 mediates T cell receptor-engaged glycolysis and restrains TFH cell differentiation.

Hsu Wei-Chan WC Chen Ming-Yu MY Hsu Shu-Ching SC Huang Li-Rung LR Kao Cheng-Yuan CY Cheng Wen-Hui WH Pan Chien-Hsiung CH Wu Ming-Sian MS Yu Guann-Yi GY Hung Ming-Shiu MS Leu Chuen-Miin CM Tan Tse-Hua TH Su Yu-Wen YW

Proceedings of the National Academy of Sciences of the United States of America 20180807 34

Activated T cells undergo metabolic reprogramming and effector-cell differentiation but the factors involved are unclear. Utilizing mice lacking DUSP6 (DUSP6-/-), we show that this phosphatase regulates T cell receptor (TCR) signaling to influence follicular helper T (TFH) cell differentiation and T cell metabolism. In vitro, DUSP6-/- CD4+ TFH cells produced elevated IL-21. In vivo, TFH cells were increased in DUSP6-/- ...[more]

PMID: 30087184

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Project description:BackgroundOur previous research revealed a novel function of berberine (BBR), a clinically relevant plant-derived alkaloid, as a suppressor of follicular T helper (Tfh) cell proliferation in secondary lymphoid organs of BBR-treated mice that underwent immunization for collagen-induced arthritis (CIA) in DBA1/J mice. Due to the importance of Tfh cell and B cell interactions in the generation of T cell-dependent humoral responses, the suppression of Tfh cell activity may have implications for the general safety of BBR as a prophylactic dietary supplement, and its potential use in antibody-driven autoimmune and hypersensitivity disorders.PurposeThis research aims to characterize BBR's impact on the activation, differentiation, and proliferation of Tfh cells by examining the expression of key extracellular signaling molecules, as well as the activity of intracellular signaling molecules involved in the Ca2+-calcineurin-NFAT pathway and STAT3 phosphorylation, following activation.Study designIn vitro experimental study using primary tissues.MethodsTo explore the direct effects of BBR on the proliferation and differentiation of Tfh cells, isolated naïve CD4+ T cells (>95% pure) were activated and differentiated into pre- Tfh cells in the presence or absence of BBR. The resulting Tfh cell populations and the expression of the key extracellular molecules CXCR5, ICOS, and PD-1 were measured. In addition, we examined the impact of BBR treatment on the activity of key intracellular signaling molecules involved in Tfh cell activation and differentiation following TCR ligation and/or CD28 signaling (p-ZAP-70, p-Lck, p-PLCγ1, NFATc1 and intracellular calcium, Ca2+, concentrations), as well as IL-6 signaling (p-STAT3).ResultsTreatment with BBR significantly reduced the expression of both CXCR5 (p < 0.01) and ICOS (p < 0.005), but not PD-1, and reduced the percentage of Tfh cells within the total CD4+ T cell population. BBR treatment also led to a reduction in intracellular Ca2+ flux, activation of p-STAT3, and IL-21 production.ConclusionOur observations provide insight into the mechanism of BBR-mediated Tfh cell suppression and suggest that BBR treatment can directly inhibit Tfh cell activity, perhaps through interfering with cytokine receptor or downstream signaling.

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DUSP6 mediates T cell receptor-engaged glycolysis and restrains T_FH cell differentiation.

Publications

DUSP6 mediates T cell receptor-engaged glycolysis and restrains T<sub>FH</sub> cell differentiation.

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