The E3 ligase VHL promotes follicular helper T cell differentiation via glycolytic-epigenetic control

• DOI: 10.1084/jem.20190337
• Publication Date: 2019-05-23T18:49:16Z
• Authors: Yangyang Zhu; Yanxia Zhao; Le Zou; Danfeng Zhang; Daisuke Aki; Yun-Cai Liu
• Keywords: Mice, Knockout; 0301 basic medicine; Ubiquitin-Protein Ligases; Cell Polarity; Fluorescent Antibody Technique; Enzyme-Linked Immunosorbent Assay; T-Lymphocytes, Helper-Inducer; Flow Cytometry; Hypoxia-Inducible Factor 1, alpha Subunit; Lymphocyte Activation; Epigenesis, Genetic; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Von Hippel-Lindau Tumor Suppressor Protein; Animals; Glycolysis; Research Articles

Follicular helper T (Tfh) cells are essential for germinal center formation and effective humoral immunity, which undergo different stages of development to become fully polarized. However, the detailed mechanisms of their regulation remain unsolved. Here we found that the E3 ubiquitin ligase VHL was required for Tfh cell development and function upon acute virus infection or antigen immunization. VHL acted through the hypoxia-inducible factor 1α (HIF-1α)−dependent glycolysis pathway to positively regulate early Tfh cell initiation. The enhanced glycolytic activity due to VHL deficiency was involved in the epigenetic regulation of ICOS expression, a critical molecule for Tfh development. By using an RNA interference screen, we identified the glycolytic enzyme GAPDH as the key target for the reduced ICOS expression via m6A modification. Our results thus demonstrated that the VHL–HIF-1α axis played an important role during the initiation of Tfh cell development through glycolytic-epigenetic reprogramming.