Metabolic inhibitors elimiante the expansion of autoimmune follicular helper T cells but not that induced by T-dependent-immunization in lupus mice

The expansion of follicular helper CD4 T (Tfh) cells is tightly associated with disease severity in lupus patients, following multiple studies in various mouse models showing that they are necessary for the production of class-switched high-affinity pathogenic autoAbs. We have recently shown that both glycolysis and mitochondrial oxidative metabolism are elevated in CD4 T cells from lupus prone B6. Sle1.Sle2.Sle3 (TC) mice as compared to B6 controls, and that a treatment combining 2-deoxy-D-glucose (2-DG), which inhibits glucose metabolism, and metformin, which inhibits oxygen consumption, normalized lupus T cell functions in vitro and reverted disease. We have expanded these results to B6. lpr , BXSB. Yaa and NZB/WF1 models of lupus. Remarkably, the number and the frequency of Tfh cells was normalized in these 4 models of lupus treated with a combination of 2DG and metformin, corresponding to a drastic reduction of autoantibodies. Treatment of normal or lupus-prone mice with the same inhibitors had however little effect on the production of TD antibodies or the expansion of Tfh cells following immunization with a nominal antigen. This suggests that Tfh cells supporting the production of autoAbs are quantitatively or qualitatively different from Tfh cells providing protective humoral immunity against pathogens. Moreover, it suggests that autoimmune Tfh cells have higher metabolic requirements than the metabolically quiescent Tfh cells that have been recently described in TD-responses. Studies to characterize the specific metabolic requirements of autoimmune Tfh cells are ongoing. Overall, our results predict that targeting Tfh cellular metabolism provides an effective and safe therapeutic approach for systemic autoimmunity.