Autoreactive and immunization-induced follicular helper T cells have opposite glucose and glutamine requirements

Abstract

Abstract Both glycolysis and mitochondrial oxidative metabolism are elevated in CD4+ T cells from lupus-prone mice, and metabolic inhibitors targeting both of these pathways normalized lupus T cell functions in vitro and reverted disease in mice. Here, we showed that inhibiting glucose metabolism with 2-deoxy-D-glucose (2DG) results in a drastic reduction of follicular helper T (TFH) cell frequency in lupus-prone B6.Sle1.Sle2.Sle3 (TC) mice. However, treatment of TC mice with 2DG had little effect on the production of antibodies or the expansion of TFH cells following immunization with a nominal antigen of T-cell-dependent (TD) humoral responses, and no effect on the frequency of influenza virus-specific TFH cells induced by immunization with PR8 influenza virus. Thus, TFH cells supporting the production of autoantibodies are different from TFH cells providing protective humoral immunity against pathogens. The specific metabolic signature from autoimmune TFH cell is significantly different compared with exogenous antigen-specific TFH cells. Further results obtained with gene expression analysis and treatment with metabolic inhibitors indicated that autoreactive TFH cells depend on glucose metabolism, while exogenous antigen-specific TFH cells are more glutamine-demanding. Overall, our results predict that targeting TFH cellular metabolism provides an effective and safe therapeutic approach for systemic autoimmunity by eliminating autoreactive TFH cells.