Expansion of Functional Regulatory T Cells Using Soluble RAGE Prevents Type 1 Diabetes

Type 1 diabetes (T1D) is an autoimmune disease with no cure. Therapeutic translation has been hampered by preclinical reproducibility. Here, short-term administration of an antagonist to the receptor for advanced glycation end products (sRAGE) protected against murine diabetes at two independent centers. Treatment with sRAGE increased regulatory T cells (T regs ) within islets, pancreatic lymph nodes and spleen, increasing islet insulin expression and function. Diabetes protection was abrogated by T reg depletion and shown to be dependent on antagonizing RAGE using knockout mice. Human T regs treated with a RAGE ligand downregulated genes for suppression, migration and T reg homeostasis ( FOXP3, IL7R, TIGIT, JAK1, STAT3, STAT5b, CCR4 ). Loss of suppressive function was reversed by sRAGE, where T regs increased proliferation and suppressed conventional T cell division, confirming that sRAGE expands functional human T regs . These results highlight sRAGE as an attractive treatment to prevent diabetes, showing efficacy at multiple research centers and in human T cells.