title: CD137 Plays Both Pathogenic and Protective Roles in Type 1 Diabetes Development in NOD Mice.
abstract: We previously reported that CD137 (encoded byTnfrsf9) deficiency suppressed type 1 diabetes (T1D) progression in NOD mice. We also demonstrated that soluble CD137 produced by regulatory T cells contributed to their autoimmune-suppressive function in this model. These results suggest that CD137 can either promote or suppress T1D development in NOD mice depending on where it is expressed. In this study, we show that NOD.Tnfrsf9-/-CD8 T cells had significantly reduced diabetogenic capacity, whereas absence of CD137 in non-T and non-B cells had a limited impact on T1D progression. In contrast, NOD.Tnfrsf9-/-CD4 T cells highly promoted T1D development. We further demonstrated that CD137 was important for the accumulation of β cell-autoreactive CD8 T cells but was dispensable for their activation in pancreatic lymph nodes. The frequency of islet-infiltrating CD8 T cells was reduced in NOD.Tnfrsf9-/-mice in part because of their decreased proliferation. Furthermore, CD137 deficiency did not suppress T1D development in NOD mice expressing the transgenic NY8.3 CD8 TCR. This suggests that increased precursor frequency of β cell-autoreactive CD8 T cells in NY8.3 mice obviated a role for CD137 in diabetogenesis. Finally, blocking CD137-CD137 ligand interaction significantly delayed T1D onset in NOD mice. Collectively, our results indicate that one important diabetogenic function of CD137 is to promote the expansion and accumulation of β cell-autoreactive CD8 T cells, and in the absence of CD137 or its interaction with CD137 ligand, T1D progression is suppressed.
authors.affiliation: Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Forsberg
authors.affiliation: Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226.
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Ciecko
authors.affiliation: Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, OH 45221.
authors.forename: Kyle J
authors.identifier: 0000-0001-5804-3415
authors.initials: KJ
authors.lastname: Bednar
authors.affiliation: Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, OH 45221.
authors.forename: Arata
authors.initials: A
authors.lastname: Itoh
authors.affiliation: Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, OH 45221.
authors.forename: Kritika
authors.initials: K
authors.lastname: Kachapati
authors.affiliation: Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, OH 45221.
authors.forename: William M
authors.initials: WM
authors.lastname: Ridgway
authors.affiliation: Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226; yichen@mcw.edu.|Max McGee National Research Center for Juvenile Diabetes, Medical College of Wisconsin, Milwaukee, WI 53226; and.|Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226.
authors.forename: Yi-Guang
authors.initials: YG
authors.lastname: Chen
mesh_terms: D053330:4-1BB Ligand / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000503:physiopathology*; D018450:Disease Progression; D050417:Insulin-Secreting Cells / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
chemical_list: D053330:4-1BB Ligand; C505975:Tnfsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9