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The CD137 Ligand Is Important for Type 1 Diabetes Development but Dispensable for the Homeostasis of Disease-Suppressive CD137+ FOXP3+ Regulatory CD4 T Cells. J Immunol 2020 06 01;204(11):2887-2899

Date

04/17/2020

Pubmed ID

32295876

Pubmed Central ID

PMC7296588

DOI

10.4049/jimmunol.1900485

Scopus ID

2-s2.0-85084888777   3 Citations

Abstract

CD137 modulates type 1 diabetes (T1D) progression in NOD mice. We previously showed that CD137 expression in CD4 T cells inhibits T1D, but its expression in CD8 T cells promotes disease development by intrinsically enhancing the accumulation of I?-cell-autoreactive CD8 T cells. CD137 is expressed on a subset of FOXP3+ regulatory CD4 T cells (Tregs), and CD137+ Tregs are the main source of soluble CD137. Soluble CD137 suppresses T cells in vitro by binding to the CD137 ligand (CD137L) upregulated on activated T cells. To further study how the opposing functions of CD137 are regulated, we successfully targeted Tnfsf9 (encoding CD137L) in NOD mice using the CRISPR/Cas9 system (designated NOD.Tnfsf9 -/-). Relative to wild-type NOD mice, T1D development in the NOD.Tnfsf9 -/- strain was significantly delayed, and mice developed less insulitis and had reduced frequencies of I?-cell-autoreactive CD8 T cells. Bone marrow chimera experiments showed that CD137L-deficient hematopoietic cells were able to confer T1D resistance. Adoptive T cell transfer experiments showed that CD137L deficiency on myeloid APCs was associated with T1D suppression. Conversely, lack of CD137L on T cells enhanced their diabetogenic activity. Furthermore, neither CD137 nor CD137L was required for the development and homeostasis of FOXP3+ Tregs. However, CD137 was critical for the in vivo T1D-suppressive activity of FOXP3+ Tregs, suggesting that the interaction between CD137 and CD137L regulates their function. Collectively, our results provide new insights into the complex roles of CD137-CD137L interaction in T1D.

Author List

Foda BM, Ciecko AE, Serreze DV, Ridgway WM, Geurts AM, Chen YG

Authors

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




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

4-1BB Ligand
Animals
CD4 Antigens
Cells, Cultured
Clustered Regularly Interspaced Short Palindromic Repeats
Diabetes Mellitus, Type 1
Forkhead Transcription Factors
Homeostasis
Humans
Immune Tolerance
Lymphocyte Activation
Mice
Mice, Inbred NOD
Mice, Knockout
Signal Transduction
T-Lymphocytes, Regulatory
Transplantation Chimera
Tumor Necrosis Factor Receptor Superfamily, Member 9