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- Title
Modulating protective and pathogenic CD4+ subsets via CD137 in type 1 diabetes.
- Authors
Irie J; Wu Y; Kachapati K; Mittler RS; Ridgway WM; Irie, Junichiro; Wu, Yuehong; Kachapati, Kritika; Mittler, Robert S; Ridgway, William M
- Abstract
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.
- Publication
Diabetes, 2007, Vol 56, Issue 1, p186
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db06-0793