LAUSR

Autoimmune diseases are life-threatening disorders that cause increasing disability over time. Systemic lupus erythematosus (SLE) and other autoimmune diseases arise when immune stimuli override mechanisms of self-tolerance. Accumulating evidence has demonstrated that protein glycosylation is substantially altered in autoimmune disease development, but the mechanisms by which glycans trigger these autoreactive immune responses are still largely unclear. In this study, we found that presence of microbial-associated mannose structures at the surface of the kidney triggers the recognition of DC-SIGN–expressing γδ T cells, inducing a pathogenic interleukin-17a (IL-17a)–mediated autoimmune response. Mice lacking Mgat5, which have a higher abundance of mannose structures in the kidney, displayed increased γδ T cell infiltration into the kidney that was associated with spontaneous development of lupus in older mice. N-acetylglucosamine supplementation, which promoted biosynthesis of tolerogenic branched N-glycans in the kidney, was found to inhibit γδ T cell infiltration and control disease development. Together, this work reveals a mannose–γδ T cell–IL-17a axis in SLE immunopathogenesis and highlights glycometabolic reprogramming as a therapeutic strategy for autoimmune disease treatment. Description Increased mannosylation drives γδ T cell infiltration into the kidney and increased IL-17a production in a mouse model of lupus. Branching out Differential glycosylation patterns on proteins are becoming increasingly implicated in inflammatory diseases. Here, Alves et al. identified aberrant mannosylation patterns on the surface of kidney cells as a potential driver of lupus nephritis. Mice lacking Mgat5 had more mannosylation on the surface of kidney cells, which was also associated with activation of IL-17a–producing γδ T cells and spontaneous development of lupus-like disease in older mice. Therapeutic supplementation of N-acetylglucosamine, which promoted tolerogenic branched N-glycan synthesis, inhibited γδ T cell-driven pathogenesis, suggesting that glycometabolic reprogramming could be a therapeutic strategy for lupus nephritis. —CM