Autoreactive B cells have a specific metabolic response during humoral responses

Abstract

Abstract Germinal centers (GC) provide a unique microenvironment for B-cell affinity maturation and class-switching recombination to occur. We compared for the first time the metabolism of B cells between lupus-prone B6.Sle1.Sle2.Sle3 (TC) mice and B6 controls at steady state, as well as during T cell-dependent (TD) and T cell-independent (TI) immunizations. B cells from TC mice showed an elevated glycolysis and mitochondrial oxidative metabolism, which was normalized by inhibiting glycolysis with in vivo 2-deoxy-D-glucose (2DG) treatment. 2DG greatly reduced the production of TI-antigen-specific antibodies, but showed minimal effect with TD-antigens. In contrast, glutaminolysis inhibition with 6-Diazo-5-oxo-L-norleucine (DON) had a greater effect on TD than TI Ag-specific antibodies in both strains. Interestingly, 2DG, but not DON reduced TI-Ag-specific IgM in TC mice, whereas both 2DG and DON prevented Ag-specific IgM production in B6 mice. Thus, autoreactive and control B cells have different intrinsic metabolic requirements. Autoreactive B cells are more glycolytic, which mirrors our previous results showing that autoreactive TFH cells have opposite glucose and glutamine requirements. The requirement for glutamine in TD-responses could be due to a direct effect on GC B cells, or an indirect effect through TFH cells. Overall, these results predict that targeting glucose metabolism provides an effective therapeutic approach for systemic autoimmunity by eliminating both autoreactive TFH and B cells, although TI-responses may be reduced in lupus-prone mice.