Type 1 diabetes (T1D) is a genetically controlled disease. While many disease-related genes have been identified in mice and humans, the mechanisms of how these genes produce T1D lags behind their identification. CD137, a T cell co-stimulatory molecule, is the protein product of Tnfrsf9, the prime Idd9.3 (Insulin dependent diabetes) T1D candidate gene. Nonobese diabetic (NOD) mice congenic for the B10 Idd9.3 haplotype (NOD.Idd9.3) are less susceptible to T1D; NOD CD137 is hypofunctional compared to B10 CD137. Our laboratories have published a series of papers on the immunological role of CD137 in T1D. On the one hand, we showed that CD137 deficient NOD mice have decreased T1D incidence, and that splenic T cells lacking CD137 are less diabetogenic. On the other hand, we found that CD137 is constitutively expressed on a subset of Tregs, and that NOD.Idd9.3 mice have increased accumulation of these CD137+ Tregs. CD137+ Tregs are more suppressive than the CD137- subset, partly due to their ability to produce an alternatively spliced CD137 variant, soluble CD137 (sCD137). NOD mice have decreased serum levels of sCD137 compared to NOD.Idd9.3 mice. We made recombinant sCD137 and showed that it prevented T1D in NOD mice. More importantly in a therapeutic context, we show here that recombinant sCD137 can halt acute T1D. We demonstrate that sCD137 directly suppresses CD4 and CD8 T cells in a CD137 Ligand (CD137L) dependent fashion. CD137L mediates ?reverse? signaling, i.e., it not only functions to activate CD137+ cells, but also signals into the CD137L expressing cell. Therefore both CD137 and CD137L actively mediate cell signaling. Active signaling by both receptor and ligand raises critical questions about the mechanism of CD137 in T1D. Hypofunctional NOD CD137 may reduce T effector action, but conversely decrease Treg function and production of immunosuppressive sCD137, thereby reducing CD137L dependent immune regulations. Thus understanding CD137 function in T1D requires defining effects in both CD137+ cells (primarily T and Treg cells) and CD137L+ cells (including APCs and T cells). In this application, we will combine the expertise of our labs to address these issues in the following specific aims. (1) Mechanisms of profound protection from T1D due to CD137 deficiency in CD8 T cells, and functional roles of CD137L expression in immunopathogenesis of T1D. (2) Mechanisms of sCD137-mediated cellular suppression and reversal of NOD new onset T1D. (3) Immunosuppressive function of human sCD137 in human immunity and T1D.

Public Health Relevance

Type 1 diabetes (T1D) is caused by autoimmune attack of pancreatic beta cells. Our proposed work will comprehensively define an immune pathway operative in T1D and define the mechanisms of a novel immunosuppressant molecule, laying the groundwork for a novel therapeutic approach to human T1D.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Spain, Lisa M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Medical College of Wisconsin
Schools of Medicine
United States
Zip Code
Chen, Yi-Guang; Mathews, Clayton E; Driver, John P (2018) The Role of NOD Mice in Type 1 Diabetes Research: Lessons from the Past and Recommendations for the Future. Front Endocrinol (Lausanne) 9:51
Cabrera, Susanne M; Engle, Samuel; Kaldunski, Mary et al. (2018) Innate immune activity as a predictor of persistent insulin secretion and association with responsiveness to CTLA4-Ig treatment in recent-onset type 1 diabetes. Diabetologia 61:2356-2370
Henschel, Angela M; Cabrera, Susanne M; Kaldunski, Mary L et al. (2018) Modulation of the diet and gastrointestinal microbiota normalizes systemic inflammation and ?-cell chemokine expression associated with autoimmune diabetes susceptibility. PLoS One 13:e0190351
Racine, Jeremy J; Stewart, Isabel; Ratiu, Jeremy et al. (2018) Improved Murine MHC-Deficient HLA Transgenic NOD Mouse Models for Type 1 Diabetes Therapy Development. Diabetes 67:923-935
Lin, Bixuan; Ciecko, Ashley E; MacKinney, Erin et al. (2017) Congenic mapping identifies a novel Idd9 subregion regulating type 1 diabetes in NOD mice. Immunogenetics 69:193-198
Forsberg, Matthew H; Ciecko, Ashley E; Bednar, Kyle J et al. (2017) CD137 Plays Both Pathogenic and Protective Roles in Type 1 Diabetes Development in NOD Mice. J Immunol 198:3857-3868