CD137 is a T cell costimulatory molecule encoded by the prime candidate gene (designated Tnfrsf9) in NOD. B10 Idd9. 3 congenic mice protected from type 1 diabetes (T1D). NOD T cells show decreased CD137-mediated T cell signaling compared with NOD. B10 Idd9. 3 T cells, but it has been unclear how this decreased CD137 T cell signaling could mediate susceptibility to T1D. We and others have shown that a subset of regulatory T cells (Tregs) constitutively expresses CD137 (whereas effector T cells do not, and only express CD137 briefly after activation). In this study, we show that the B10 Idd9. 3 region intrinsically contributes to accumulation of CD137+ Tregs with age. NOD. B10 Idd9. 3 mice showed significantly increased percentages and numbers of CD137+ peripheral Tregs compared with NOD mice. Moreover, Tregs expressing the B10 Idd9. 3 region preferentially accumulated in mixed bone marrow chimeric mice reconstituted with allotypically marked NOD and NOD. B10 Idd9. 3 bone marrow. We demonstrate a possible significance of increased numbers of CD137+ Tregs by showing functional superiority of FACS-purified CD137+ Tregs in vitro compared with CD137− Tregs in T cell-suppression assays. Increased functional suppression was also associated with increased production of the alternatively spliced CD137 isoform, soluble CD137, which has been shown to suppress T cell proliferation. We show for the first time, to our knowledge, that CD137+ Tregs are the primary cellular source of soluble CD137. NOD. B10 Idd9. 3 mice showed significantly increased serum soluble CD137 compared with NOD mice with age, consistent with their increased numbers of CD137+ Tregs with age. These studies demonstrate the importance of CD137+ Tregs in T1D and offer a new hypothesis for how the NOD Idd9. 3 region could act to increase T1D susceptibility.