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 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.
Irie
Junichiro
J
Division of Rheumatology and Immunology, University of Pittsburgh School of Medicine, PA, USA.
Wu
Yuehong
Y
Kachapati
Kritika
K
Mittler
Robert S
RS
Ridgway
William M
WM
D000818:Animals; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control; D017710:Lymphocyte Transfusion; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000276:immunology*
D001323:Autoantibodies; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9