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Modulating Protective and Pathogenic CD4⁺ Subsets via CD137 in Type 1 Diabetes

¹ Division of Rheumatology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
² Department of Surgery and Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia

Address correspondence and reprint requests to William M. Ridgway, S725 Biomedical Science Tower, 3500 Terrace St., Pittsburgh, PA 15261. E-mail: ridgway2{at}pitt.edu

Abbreviations: APC, antigen-presenting cell; EAE, experimental autoimmune encephalomyelitis; ELISA, enzyme-linked immunosorbent assay; IBD, inflammatory bowel disease; IFN-, interferon-; IL, interleukin; MHC, major histocompatibility complex; SLE, systemic lupus erythematosus; TNF, tumor necrosis factor; Treg, T regulatory

CD137 (TNFRSF9) is an activation-inducible T-cell costimulatory molecule and a member of the tumor necrosis factor (TNF) receptor superfamily. Cd137 is also a candidate gene (in the Idd9.3 interval) for autoimmune diabetes in NOD mice. Here, we demonstrate that anti-CD137 treatment protects NOD mice from diabetes. Anti-CD137–treated mice are not protected from insulitis and still harbor pathogenic T-cells, as demonstrated by transfer studies. Transfer of CD4⁺, but not CD8⁺, cells from anti-CD137–treated pre-diabetic NOD mice into NOD-scid mice delayed diabetes onset. Anti-CD137 treatment significantly increased the number of CD4⁺CD25⁺ cells, which demonstrated intracellular Foxp3 expression and in vitro suppressive activity. The CD4⁺CD25⁺ cell subset from anti-CD137–treated mice transferred complete protection from diabetes, whereas the CD4⁺CD25^– cell subset offered no significant protection. Anti-CD137 treatment of NOD-scid recipients of diabetic spleen cells, however, hastened the onset of disease, showing that the effect of anti-CD137 treatment depends on the balance of pathogenic and protective cells. These results support a critical role for CD137 acting in the early phase of autoimmune diabetes to enhance regulatory cell production. Disease-associated CD137 alleles are likely ineffectual at stimulating a regulatory T-cell population sufficient to prevent disease.

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