Enhanced N-glycan branching on CD8 T cells exacerbates autoimmune diabetes in non-obese diabetic mice

Abstract

Abstract β1,6N-acetylglucosaminyltransferase V (Mgat5), is responsible for tetra-antennary N-glycans in the biosynthesis of glycoprotein and the resultant N-glycan branching serves as a backbone for additional glycosylation such as poly-N-aceyllactosamine (poly-LacNAc) structure. The N-glycan branching is involved in the pathological conditions such as malignancies, but the modulatory roles of N-glycan branching on T cells in autoimmune diabetes is not completely understood. Here, we report that the levels of N-glycan branching on T cells is positively correlated with the diabetogenesis in NOD mice. Since the levels of N-glycan branching is regulated during T-cell development and highly increases in pathogenic lymphocytes in pancreas, we generated established T cell-specific Mgat5 transgenic and mutant NOD mice. Interestingly, our results demonstrated that the diabetic incidence in Mgat5 transgenic mice was significantly higher and that of Mgat5 mutant mice markedly attenuated compared to control NOD mice. In adoptive transfer experiments, NOD/SCID mice that received control CD4 T cells plus transgenic CD8 T cells developed diabetes more rapidly than the mice received control or transgenic CD4 T cells plus control CD8 T cells, suggesting that the diabetogenicity in Mgat5 transgenic mice is a CD8 T cell–autonomous manner. Moreover, we generated Mgat5/NY8.3 doubly transgenic NOD mice expressing highly pathogenic MHC class-I-restricted 8.3 T cell receptor, and observed that these mice have higher diabetic incidence than wild-type NY8.3 transgenic NOD mice. Taken together, enhanced N-glycan branching on CD8 T cells exacerbates the development of diabetes in NOD mice.