Gm2a as a novel regulator of CD8 +T cell threshold of activation in transplantation

Abstract Transplant patients must remain on toxic immunosuppression for life, underscoring the need to identify immunotherapeutic targets that may facilitate transplant tolerance. We recently showed kidney recipients remained stable following withdrawal of mainstay exhibited increased levels glycosphingolipid-catabolizing protein Gm2a, specifically in CD8 +T cells, compared who went reject their allografts. While role Gm2a lysosomal glycosphingolipid degradation neurons is well known, little known about function immune system. To investigate this, we performed skin graft surgery WT vs −/−mice. Results show deficiency significantly allograft rejection relative counterparts. Moreover, adoptive transfer donor-reactive vs. −/−CD8 cells into hosts resulted accumulation T and accelerated as cells. This was likely due proliferation, vitro studies revealed enhanced proliferation CTV-labeled −/−vs. Interestingly, K b/SIINFEKL tetramer staining sustained TCR expression antigen stimulation Finally, responsiveness low dose low-affinity peptide In conclusion, these results a novel, cell-intrinsic regulator cell activation threshold directly impacts cell-mediated rejection. Supported by grants from NIH (R01AI164716)