Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
Front Immunol. 2023 Mar 13;14:1140426. doi: 10.3389/fimmu.2023.1140426. eCollection 2023.
This study provides evidence of how Th1 cell metabolism is modulated by the purinergic receptor P2X7 (P2RX7), a cation cannel activated by high extracellular concentrations of adenosine triphosphate (ATP).
analysis was performed in the Plasmodium chabaudi model of malaria in view of the great relevance of this infectious disease for human health, as well as the availability of data concerning Th1/Tfh differentiation.
We show that P2RX7 induces T-bet expression and aerobic glycolysis in splenic CD4+ T cells that respond to malaria, at a time prior to Th1/Tfh polarization. Cell-intrinsic P2RX7 signaling sustains the glycolytic pathway and causes bioenergetic mitochondrial stress in activated CD4+ T cells. We also show the phenotypic similarities of Th1-conditioned CD4+ T cells that do not express P2RX7 and those in which the glycolytic pathway is pharmacologically inhibited. In addition, ATP synthase blockade and the consequent inhibition of oxidative phosphorylation, which drives cellular metabolism for aerobic glycolysis, is sufficient to promote rapid CD4+ T cell proliferation and polarization to the Th1 profile in the absence of P2RX7.
These data demonstrate that P2RX7-mediated metabolic reprograming for aerobic glycolysis is a key event for Th1 differentiation and suggest that ATP synthase inhibition is a downstream effect of P2RX7 signaling that potentiates the Th1 response.
本研究提供了证据表明，嘌呤能受体 P2X7（P2RX7）如何调节 Th1 细胞代谢，P2RX7 是一种阳离子通道，可被细胞外高浓度的三磷酸腺苷（ATP）激活。
鉴于这种传染病对人类健康具有重要意义，以及有关 Th1/Tfh 分化的数据，我们在疟原虫感染的伯氏疟原虫模型中进行了分析。
我们表明，P2RX7 在疟原虫感染的脾 CD4+T 细胞中诱导 T 细胞因子（T-bet）表达和有氧糖酵解，这发生在 Th1/Tfh 极化之前。细胞内固有 P2RX7 信号通路维持糖酵解途径，并导致激活的 CD4+T 细胞中的生物能线粒体应激。我们还显示了不表达 P2RX7 的 Th1 条件性 CD4+T 细胞与那些糖酵解途径被药理抑制的细胞具有相似的表型。此外，ATP 合酶阻断和随之而来的氧化磷酸化抑制，这驱动了有氧糖酵解的细胞代谢，足以在没有 P2RX7 的情况下促进 CD4+T 细胞的快速增殖和向 Th1 表型的极化。
这些数据表明，P2RX7 介导的有氧糖酵解代谢重编程是 Th1 分化的关键事件，并表明 ATP 合酶抑制是 P2RX7 信号的下游效应，增强了 Th1 反应。
