Linking Ganglioside Metabolism to Immune Tolerance: Insights into Treg Biology 9258

Abstract Description Addressing the challenges of lifelong immunosuppression in transplant patients requires innovative approaches to achieve immune tolerance. A transcriptomic screen of kidney transplant recipients revealed higher levels of the glycosphingolipid-catabolizing protein GM2 activator protein (Gm2a) in stable patients compared to those who rejected their allografts. Although Gm2a’s role in neuronal glycosphingolipid metabolism is well-known, its immune function is largely unexplored. To determine the mechanistic role of Gm2a in allograft rejection, we utilized a skin transplant model and found that Gm2a-/- mice exhibited significantly accelerated allograft rejection compared to WT controls. Post-transplant analysis revealed a marked reduction in Treg frequency within the blood, DLN, and graft of Gm2a-/- mice compared to WT controls. Using human PBMCs, we found that Foxp3+ Tregs expressed the highest levels of Gm2a of all T cell subsets, consistent with published studies demonstrating Gm2a was enriched in CD4+CD25+ T cells associated with tolerance. Functional assays revealed that Gm2a deficiency impaired the suppression of CD69 upregulation in vitro, while Gm2a deficiency also resulted in an increased frequency of Foxp3+ Tregs in the thymus. These findings indicate that Gm2a plays a role in modulating both Treg development and function and suggest it could be a promising target for strategies aimed at promoting transplant tolerance and reducing the need for lifelong immunosuppression. Funding Sources R01 AI 164716 Topic Categories Transplantation Immunology (TRAN)