The role of CD137+ T regulatory cells in controlling T1D

Abstract

CD4+CD25+Foxp3+ Tregs maintain immunologic tolerance and are important in diabetes pathogenesis in non‐obese diabetic (NOD) mice. NOD.B10 Insulin dependent diabetes (Idd) 9.3 congenic mice are protected from diabetes; CD137 is the major Idd9.3 candidate gene. We published that treatment of NOD mice with an agonist anti‐CD137 antibody (3H3) prevented diabetes through expansion of Tregs in vivo. Here we show that depletion of Tregs with anti‐CD25 abolished 3H3 mediated prevention of diabetes, confirming that anti‐CD137 antibody targets Tregs. A subset of Tregs constitutively expresses CD137. We showed that CD137+ Tregs produce significantly higher levels of IL‐10 and CD69 than CD137‐ Tregs, but the levels of TGF‐b1, Foxp3 and CD62L are similar between subsets. NOD.scid recipients of anti‐CD25 treated splenocytes from NOD.Idd9.3 mice develop diabetes, suggesting that Tregs play a role in protection from diabetes in NOD.Idd9.3 mice. We show an age dependent decline in CD137+ Tregs in NOD, but not in NOD.Idd9.3 congenic mice. In concordance with studies that link CD137 with long term survival, we have observed that CD137+ Tregs express higher levels of mRNA for anti‐apoptotic molecule Bcl2, indicating that CD137 co‐stimulation is important for in‐vivo survival of Tregs. CD137 co‐stimulation of Tregs is hence important in balancing pathogenic effectors and preventing Type 1 Diabetes (T1D) in the NOD model.