Mechanical force receptor Piezo1 regulates TH9 cell differentiation

Interleukin (IL)-9-producing CD4+ T cells (TH9) are essential for mediating antitumor immunity, but the mechanisms of TH9 cell differentiation remain unclear. Here, we found that the mechanical force receptor Piezo1 is critical for regulating TH9 cell differentiation. Piezo1 deficiency in CD4+ T cells intrinsically inhibited TH9 cell differentiation, whereas ectopic Piezo1 expression promoted this process. Notably, Piezo1 deficiency inhibited TH9 cell differentiation and contributed to tumor development. Mechanistically, Piezo1 deficiency inhibits TH9 cell differentiation mainly through the SIRT3-succinate dehydrogenase A (SDHA)-oxidative phosphorylation (OXPHOS) pathway. SIRT3 deficiency or blockade of SDHA-OXPHOS signaling activity reversed the TH9 cell differentiation induced by Piezo1 deficiency. Moreover, HIF1a signaling is responsible for the TH9 cell differentiation induced by Piezo1 deficiency. Thus, our findings identify a redox metabolism signaling mechanism regulated by the mechanical force receptor Piezo1 that limits the mitochondrial SIRT3-SDHAdependent OXPHOS pathway and triggers HIF1a-IL-9 to reprogram TH9 cell differentiation, with implications for future immunotherapy approaches.