Soluble RAGE Prevents Type 1 Diabetes Expanding Functional Regulatory T Cells

Leung, Sherman S., Borg, Danielle J., McCarthy, Domenica A., Boursalian, Tamar E., Cracraft, Justen, Zhuang, Aowen, Fotheringham, Amelia K., Flemming, Nicole, Watkins, Thomas, Miles, John J., Groop, Per-Henrik, Scheijen, Jean L., Schalkwijk, Casper G., Steptoe, Raymond J., Radford, Kristen J., Knip, Mikael, and Forbes, Josephine M. (2022) Soluble RAGE Prevents Type 1 Diabetes Expanding Functional Regulatory T Cells. Diabetes, 71 (9). pp. 1994-2008.

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Abstract

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 (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 with use of 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.

Item ID: 76439
Item Type: Article (Research - C1)
ISSN: 1939-327X
Copyright Information: © 2022 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/journals/pages/license.
Funders: National Health and Medical Research Council (NHMRC), Australian Research Council (ARC)
Projects and Grants: NHMRC 1023661, ARC FT110100372, NHMRC 1004503, NHMRC 1102935
Date Deposited: 13 Mar 2023 07:10
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320403 Autoimmunity @ 100%
SEO Codes: 20 HEALTH > 2001 Clinical health > 200105 Treatment of human diseases and conditions @ 100%
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