A gatekeeper of CD8+ T cell sensitivity: GM2A regulates TCR expression and limits CD8+ T cell threshold of activation 3233

Abstract Description T cell sensitivity to antigen is a critical parameter in controlling T cell-mediated immunity. However the molecular mechanisms are incompletely understood. Here, we identified a novel regulator of TCR expression that restrains antigen sensitivity of CD8+ T cells. In a transcriptomic screen of renal transplant recipients who were weaned from immunosuppression, we found increased expression of glycosphingolipid-catabolizing protein (Gm2a) in CD8+ T cells from stable patients vs. those that went on to reject. Using an OVA-expressing skin graft model to investigate the role of Gm2a in regulating CD8+ T cell immunity, we found that Gm2a-/- OT-I CD8+ T cells exhibited increased accumulation and mediated accelerated allograft rejection vs WT OT-I, illuminating a CD8+ T cell-intrinsic role for Gm2a. Analysis of the endogenous CD8+ T cell response to alloantigen revealed a 50% augmentation in the frequency of alloreactive precursors among Gm2a-/- vs CD8+ T cells. TCR sequencing analysis demonstrated that Gm2a deficiency increased the number and diversity of alloreactive CD8+ T cell clones. Mechanistically, Gm2a-/- CD8+ T cells exhibited sustained TCR expression upon activation compared to WT cells, conferring increased responsiveness to low-affinity and low-dose antigens. Finally, treating PBMCs with exogenous GM2A reduced CD8+ T cell proliferation vs. control. Therefore, we show for the first time that Gm2a attenuates CD8+ T cell sensitivity to Ag by reducing surface TCR expression. Funding Sources 5R01AI164716-03 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)