Modulating protective and pathogenic CD4⁺ subsets via CD137 in type 1 diabetes

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 NODscid 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.