HIF1α-Dependent Metabolic Signals Control the Differentiation of Follicular Helper T Cells

Follicular helper T (T-FH) cells are critical for germinal center (GC) formation and are responsible for effective B cell-mediated immunity; metabolic signaling is an important regulatory mechanism for the differentiation of T-FH cells. However, the precise roles of hypoxia inducible factor (HIF) 1 alpha-dependent glycolysis and oxidative phosphorylation (OXPHOS) metabolic signaling remain unclear in T-FH cell differentiation. Herein, we investigated the effects of glycolysis and OXPHOS on T-FH cell differentiation and GC responses using a pharmacological approach in mice under a steady immune status or an activated immune status, which can be caused by foreign antigen stimulation and viral infection. GC and T-FH cell responses are related to signals from glycolytic metabolism in mice of different ages. Foreign, specific antigen-induced GC, and T-FH cell responses and metabolic signals are essential upon PR8 infection. Glycolysis and succinate-mediated OXPHOS are required for the GC response and T-FH cell differentiation. Furthermore, HIF1 alpha is responsible for glycolysis- and OXPHOS-induced alterations in the GC response and T-FH cell differentiation under steady or activated conditions in vivo. Blocking glycolysis and upregulating OXPHOS signaling significantly recovered T-FH cell differentiation upon PR8 infection and ameliorated inflammatory damage in mice. Thus, our data provide a comprehensive experimental basis for fully understanding the precise roles of HIF1 alpha-mediated glycolysis and OXPHOS metabolic signaling in regulating the GC response and T-FH cell differentiation during stable physiological conditions or an antiviral immune response.