Metabolic regulation of the germinal center reaction in murine chronic graft versus host disease

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) following chemotherapy is a potent therapy for multiple hematopoietic diseases and malignancies. However, the efficacy of long-term allo-HSCT is limited by the development of graft-versus-host-disease (GVHD). In cGVHD, donor derived T cells can differentiate into T follicular helper cells (TFH) that interact with germinal center B cells (GCB) to facilitate the production of alloreactive class switched antibodies. Patients refractory to the standard treatment regimens have a poor prognosis indicating an urgent need for new therapies. In these studies, we sought to explore the metabolic regulation of TFH and GCB to identify selective therapeutic approaches to treat cGVHD. We utilized a multi-organ mouse model of cGVHD that manifests bronchiolitis obliterans (BO). First, we determined that as cGVHD progresses, TFH undergo a shift from relying on glycolysis towards oxidative phosphorylation (OXPHOS). Through metabolomics, cGVHD TFH had evidence of increased catabolism suggesting replenishment of tricarboxylic acid (TCA) cycle intermediates. This informed our investigation of mitochondrial pyruvate carrier (MPC) inhibitors which resulted in a significant improvement in cGVHD. Second, we sought to determine how GCB undergo metabolic reprogramming within the context of cGVHD. We determined that as cGVHD progresses, GCB increase ROS production, and the utilization of fatty acids and amino acids indicating increased OXPHOS. Through metabolomics we found an increased abundance of metabolites involved in the pentose phosphate pathway, purine metabolism, and phospholipoids in cGVHD GCB, indicating reprogrammed energy utilization to support the highly energetic demands of the germinal center reaction as cGVHD progresses. Overall, these studies help to better elucidate the metabolic processes fueling pathogenic TFH and GCB function during cGVHD, informing novel immunometabolic therapeutic approaches.