The E3 Ligase VHL Promotes The Differentiation And Function Of Follicular Helper T Cells Through Glycolytic-epigenetic Pathways

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.Tfh cells are localized in B cell follicles and provide multiple signals to B cells to form GCs where GC B cells undergo somatic hypermutation,affinity maturation,antibody class switching,and differentiation into high-affinity plasma cells and long-lived memory cells.A combination of signals and transcription factors are required for the initiation,commitment and maintenance of Tfh cells.Hypoxic responses and dynamic regulation of metabolism have been implicated in the regulation of various immune cells.The VHL-HIF1? axis responses to the changes of local oxygen level,which then leads to functional and metabolic adaptations to hypoxic microenvironments in mammalian cells.It is known that lymphoid tissues are exposed to different oxygen gradients under physiological and inflamed conditions.Particularly,the GCs have been shown to be an extremely hypoxic site.It is still unknown whether VHL-HIF axis controls the development and function of Tfh cells in the lymphoid microenvironments.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)-1a-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 the sh RNAmir-based screen,we identified the glycolytic enzyme GAPDH as the key target for the reduced ICOS expression via m~6A modification during Tfh cell initiation.Our results thus demonstrated that VHL-HIF1? axis played an important role during the initiation of Tfh cell development through glycolytic-epigenetic reprogramming,which can provide some insight into rational vaccine design against human infectious diseases and therapeutic intervention of autoimmune diseases.