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

  • Immunity. 2026 Jul 14;59(7):1911-1927.e12. doi: 10.1016/j.immuni.2026.04.009.
Lai Wang  1 ,  Jiao Jiang  2 ,  Haoyuan Yin  1 ,  Junhui Wu  3 ,  Xiaoyu Su  3 ,  Lingchang Meng  4 ,  Lulu Wang  5 ,  Jingjing Bao  6 ,  Qilin Li  2 ,  Yunbo Wei  7 ,  Zhian Chen  8 ,  Jialei Gong  8 ,  Pablo F Cañete  9 ,  Meiling Zheng  2 ,  Wenrui Li  2 ,  Qiongqiong Zhou  10 ,  Ming Zhao  11 ,  Di Yu  12 ,  Qianjin Lu  13
Affiliations
  • 1. Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu 210042, China; Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, Jiangsu 210042, China; Jiangsu Provincial Key Laboratory of Dermatology, Nanjing, Jiangsu 210042, China.
  • 2. Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu 210042, China; Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, Jiangsu 210042, China.
  • 3. Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, Jiangsu 210042, China.
  • 4. Institute of Chinese Medicine, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China.
  • 5. Department of Pharmacy, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China.
  • 6. Clinical Laboratory, Nanjing Red Cross Blood Center, Nanjing, Jiangsu 210001, China.
  • 7. Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong 250014, China.
  • 8. Frazer Institute, Faculty of Health, Medicine and Behaviour Sciences, The University of Queensland, Brisbane, QLD 4102, Australia.
  • 9. Frazer Institute, Faculty of Health, Medicine and Behaviour Sciences, The University of Queensland, Brisbane, QLD 4102, Australia; Ian Frazer Centre for Children's Immunotherapy Research, Children's Health Research Centre, Faculty of Health, Medicine and Behaviour Sciences, The University of Queensland, Brisbane, QLD 4101, Australia.
  • 10. Otolaryngology department, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu 210019, China.
  • 11. Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu 210042, China; Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, Jiangsu 210042, China; Jiangsu Provincial Key Laboratory of Dermatology, Nanjing, Jiangsu 210042, China. Electronic address: [email protected].
  • 12. Frazer Institute, Faculty of Health, Medicine and Behaviour Sciences, The University of Queensland, Brisbane, QLD 4102, Australia; Ian Frazer Centre for Children's Immunotherapy Research, Children's Health Research Centre, Faculty of Health, Medicine and Behaviour Sciences, The University of Queensland, Brisbane, QLD 4101, Australia. Electronic address: [email protected].
  • 13. Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu 210042, China; Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, Jiangsu 210042, China; Jiangsu Provincial Key Laboratory of Dermatology, Nanjing, Jiangsu 210042, China; Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan 410013, China. Electronic address: [email protected].
PMID: 42134327 DOI: 10.1016/j.immuni.2026.04.009
Abstract

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.

Keywords
CXCR5; RAB35; T follicular helper cells; autoimmune diseases; geranylgeranyl diphosphate; pitavastatin; surface protein expression.
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