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Soluble RAGE Prevents Type 1 Diabetes Expanding Functional Regulatory T Cells

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posted on 17.06.2022, 15:28 authored by Sherman S. Leung, Danielle J. Borg, Domenica A. McCarthy, Tamar E. Boursalian, Justen Cracraft, Aowen Zhuang, Amelia K. Fotheringham, Nicole Flemming, Thomas Watkins, John J. Miles, Per-Henrik Groop, Jean L. Scheijen, Casper G. Schalkwijk, Raymond J. Steptoe, Kristen J. Radford, Mikael Knip, Josephine M. Forbes

 Type 1 diabetes (T1D) 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 (Tregs) within the islets, pancreatic lymph nodes and spleen, increasing islet insulin expression and function. Diabetes protection was abrogated by Treg depletion and shown to be dependent on antagonizing RAGE using knockout mice. Human Tregs treated with a RAGE ligand downregulated genes for suppression, migration and Treg homeostasis (FOXP3, IL7R, TIGIT, JAK1, STAT3, STAT5b, CCR4). Loss of suppressive function was reversed by sRAGE, where Tregs increased proliferation and suppressed conventional T cell division, confirming that sRAGE expands functional human Tregs. These results highlight sRAGE as an attractive treatment to prevent diabetes, showing efficacy and reproducibility at multiple research centers and in human T cells. 

Funding

This work was supported by the NHMRC (1023661), JDRF (5-2010-163), Diabetes Australia, The Victorian Government Infrastructure Program and Mater Foundation. S.S.L. was supported by the Research Training Program and JDRF; A.K.F. and N.F. by the Research Training Program; A.Z. by Kidney Health Australia; R.J.S. by an ARC Fellowship (FT110100372); and J.M.F. by NHMRC Fellowships (1004503, 1102935).

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