Itaconate regulates metabolic reprogramming of Th1 cells and alleviates acute graft-versus-host disease 3353

Description Acute graft-versus-host disease (aGVHD) is one of the major complications after allo-HSCT, which is caused by the differentiation of pathogenic T cells. Recent studies have demonstrated that Itaconate (ITA) regulates macrophage polarization and inhibits anti-tumoral CD8+T cell responses. However, the role of ITA in pathogenic T cell activity followed allo-HSCT remains unknown. Here, we found ITA significantly mitigates aGVHD development and represses T cell activation in recipients. ITA directly inhibits Th1 polarization, T-bet expression, and IFN-g production in vitro. scRNA-seq and Seahorse assay showed that ITA regulates Th1 metabolic reprogramming. ITA significantly upregulates nucleotides, including glycine, arginine, and proline, while downregulates SAM production. 13C-glucose and 13C,15N-methione tracking revealed ITA treatment suppressed one carbon metabolism in Th1 cells. Th1 differentiation was decreased after inhibition of the key enzymes involved in one carbon metabolism. Furthermore, ITA inhibits histone methylation in Th1 cells. ATAC-seq and CUT&Tag were performed to dissect the epigenetic regulation of ITA. SAM production and Th1 differentiation were decreased after ROS elimination. Nrf2 blockage diminished the role of ITA in Th1 differentiation and aGVHD-related survival. Collectively, we demonstrated that ITA regulates ROS scavenging and restricts one-carbon metabolism in Th1 through Nrf2, thereby mitigating aGVHD development.