Mitochondrial pyruvate carrier inhibition restrains germinal center T follicular helper cells attenuating chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. During cGVHD, T follicular helper cells (TFH) and germinal center B-cells (GCB) interactions produce pathogenic class-switched allo- and auto-antibodies. We utilized a multi-organ cGVHD mouse model with bronchiolitis obliterans (BO) to investigate TFH metabolism and metabolic vulnerabilities at early and late times post-transplant. We found that TFH were highly glycolytic early in cGVHD/BO progression but later transitioned to a more oxidative metabolic profile. The mitochondrial pyruvate carrier (MPC) transports pyruvate into the mitochondria, directly linking glycolysis to mitochondrial oxidative phosphorylation (OXPHOS). To disrupt the TFH glycolysis to OXPHOS transition that accompanies cGVHD/BO progression, we tested 7ACC2, a potent MPC inhibitor, in ex vivo and in vivo cGVHD-related assays. In a co-culture assay, 7ACC2 significantly reduced TFH:B dependent class-switched immunoglobulin production. In vivo, mice with established cGVHD/BO given 7ACC2 from days 28-49 significantly improved pulmonary function associated with lower TFH and GCB frequencies. Because MPC inhibitors are tested in clinical trials to treat metabolic diseases, cancer and neurodegenerative disease, clinical trials to test this novel MPC-based approach to stifle TFH metabolic demands in patients with treatment refractory cGVHD/BO progression warrants future consideration.