Modulation of the mevalonate pathway by TCR engagement regulates T follicular helper cell generation in homeostasis and autoimmunity.

Surface proteins enable T follicular helper (Tfh) cells' chemotactic migration toward B cells and subsequent functional interactions, underpinning effective humoral immunity. We showed that geranylgeranyl diphosphate (GGPP), a mevalonate (MVA) pathway-derived isoprenoid, was indispensable for Tfh cell function by maintaining surface protein expression. Either pharmacological inhibition or genetic depletion of geranylgeranyl diphosphate synthase (GGPS1), the enzyme responsible for GGPP biosynthesis, impaired Tfh cell generation. Mechanistically, geranylgeranyl transferase Ⅱ (GGTase Ⅱ) utilizes GGPP to geranylgeranylate RAB GTPases for surface protein expression, as exemplified by RAB35-mediated recycling of the chemokine receptor CXCR5 to the cell surface. Notably, the MVA pathway-GGPS1-GGTase Ⅱ-RAB35 axis in Tfh cells was enhanced by T cell receptor signaling and hyperactivated in autoimmunity. Conversely, the potent statin pitavastatin inhibited this axis to suppress pathogenic Tfh cells and alleviate autoimmunity. Thus, GGPP links the MVA pathway to T cell function via surface protein regulation, revealing a therapeutic target for autoimmune diseases.