The B10 Idd9.3 locus mediates accumulation of functionally superior CD137pos T regulatory cells in the NOD Type 1 diabetes model

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 one diabetes (T1D). NOD T cells show decreased CD137-mediated T cell signaling compared to 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 T regulatory cells (Tregs) constitutively expresses CD137 (whereas T effectors do not, and only express CD137 briefly after activation). Here we show that the B10 Idd9.3 region intrinsically contributes to accumulation of CD137 pos Tregs with age. NOD.B10 Idd9.3 mice showed significantly increased percentages and numbers of CD137 pos peripheral Tregs compared to 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 pos Tregs by showing functional superiority of FACS purified CD137 pos Tregs in vitro compared to CD137 neg 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 that CD137 pos Tregs are the primary cellular source of soluble CD137. NOD.B10 Idd9.3 mice showed significantly increased serum soluble CD137 compared to NOD mice with age, consistent with their increased numbers of CD137 pos Tregs with age. These studies demonstrate the importance of CD137 pos Tregs in T1D and offer a new hypothesis for how the NOD Idd9.3 region could act to increase T1D susceptibility.