Soluble RAGE Prevents Type 1 Diabetes Expanding Functional Regulatory T Cells

Type 1 diabetes is an autoimmune disease with no cure, where clinical translation of promising therapeutics has been hampered by the reproducibility crisis. Here, short-term administration of an antagonist to the receptor for advanced glycation end products (sRAGE) protected against murine diabetes at two independent research centers. Treatment with sRAGE increased regulatory T cells (T-regs) within the 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 with use of 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 and reproducibility at multiple research centers and in human T cells.