Glucose Uptake by Germinal Center B Cells Selectively Sustains Autoimmunity While Sparing Responses to Foreign Antigens 2255581

Abstract Introduction Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that features persistent germinal center (GC) formation and pathogenic autoantibody production. While healthy GC B cells rely primarily on fatty acid oxidation for energy, we showed that blocking glycolysis with 2-deoxyglucose (2DG) selectively inhibited autoreactive, but not foreign antigen-specific, GC B cells. Here, we directly tested whether this glycolytic bias corresponds to an intrinsic requirement of autoimmune GC B cells. Methods We generated GC-specific GLUT1-deficient mice (GLUT1 f/f Aicda-Cre) on healthy C57BL/6 (B6-cKO) and autoimmune Sle1b (Sle1b-cKO) backgrounds. B6 and B6-cKO mice were subjected to five weeks of bm12-induced chronic graft-versus-host disease (cGVHD) or immunized once with NP-OVA/alum to model lupus-like and primary foreign-antigen responses, respectively. For recall responses, B6, B6-cKO, Sle1b, and Sle1b-cKO mice were primed and boosted with NP-OVA/alum. Splenocytes were analyzed by flow cytometry and serum anti-NP antibodies were assessed by ELISA. Results GLUT1 loss markedly reduced the expansion of GC B cells and T follicular helper cells, and eliminated autoantibody production in the cGVHD model, while GC and antibody responses to primary immunization with NP-OVA remained intact. In the recall cohort, GLUT1 deletion in Sle1b mice eliminated the expanded NP⁻ (autoreactive) GC B cell subset, reducing it to B6 levels, while NP+ GC B cell frequency and NP-specific antibody titers remained unchanged across B6 and Sle1b backgrounds. Conclusion Across primary and memory NP-OVA responses, GC B-cell GLUT1 is dispensable for foreign-antigen GC B cell frequency, class switching, and affinity maturation. In contrast, GLUT1 is selectively required to sustain autoreactive GC B cells. With current therapies still limited by broad immunosuppression, targeting B-cell metabolism may redefine lupus treatment, silencing autoimmunity while preserving host defense. Funding Source NIH/NIAID R37AI128901; NIH T32GM113896; NIH T32GM145432 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)