The E3 ligase VHL promotes the differentiation of follicular helper T cells through glycolytic-epigenetic pathways

Abstract 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 hypoxia-inducible factor (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 cell development. By using the RNAi-based screen, we identified the glycolytic enzyme GAPDH as the key target for the reduced ICOS expression via m6A modification during Tfh cell initiation. Our results thus demonstrated that VHL-HIF-1α axis played an important role during the initiation of Tfh cell development through glycolytic-epigenetic reprogramming. Here we will discuss how immune signals and cell metabolic programs are linked to instruct Tfh cell initiation and function, which can provide some insight into rational vaccine design against human infectious diseases and therapeutic intervention of autoimmune diseases.