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CD137 Plays Both Pathogenic and Protective Roles in Type 1 Diabetes Development in NOD Mice. J Immunol 2017 05 15;198(10):3857-3868

Date

04/02/2017

Pubmed ID

28363905

Pubmed Central ID

PMC5426805

DOI

10.4049/jimmunol.1601851

Scopus ID

2-s2.0-85019711824   12 Citations

Abstract

We previously reported that CD137 (encoded by Tnfrsf9) 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 I? 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 I? 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 I? cell-autoreactive CD8 T cells, and in the absence of CD137 or its interaction with CD137 ligand, T1D progression is suppressed.

Author List

Forsberg MH, Ciecko AE, Bednar KJ, Itoh A, Kachapati K, Ridgway WM, Chen YG

Author

Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

4-1BB Ligand
Animals
CD8-Positive T-Lymphocytes
Cell Proliferation
Diabetes Mellitus, Type 1
Disease Progression
Insulin-Secreting Cells
Mice
Mice, Inbred NOD
Mice, Transgenic
T-Lymphocytes, Regulatory
Tumor Necrosis Factor Receptor Superfamily, Member 9