Soluble CD137 Ameliorates Acute Type 1 Diabetes by Inducing T Cell Anergy. Front Immunol 2019;10:2566
Date
12/04/2019Pubmed ID
31787971Pubmed Central ID
PMC6853870DOI
10.3389/fimmu.2019.02566Scopus ID
2-s2.0-85075568372 (requires institutional sign-in at Scopus site) 23 CitationsAbstract
We show here that soluble CD137 (sCD137), the alternately spliced gene product of Tnfsfr9, effectively treats acute type 1 diabetes (T1D) in nonobese diabetic (NOD) mice. sCD137 significantly delayed development of end-stage disease, preserved insulin+ islet beta cells, and prevented progression to end-stage T1D in some mice. We demonstrate that sCD137 induces CD4+ T cell anergy, suppressing antigen-specific T cell proliferation and IL-2/IFN-γ secretion. Exogenous IL-2 reversed the sCD137 anergy effect. sCD137 greatly reduces inflammatory cytokine production by CD8 effector memory T cells, critical mediators of beta cell damage. We demonstrate that human T1D patients have decreased serum sCD137 compared to age-matched controls (as do NOD mice compared to NOD congenic mice expressing a protective Tnfsfr9 allele), that human sCD137 is secreted by regulatory T cells (Tregs; as in mice), and that human sCD137 induces T cell suppression in human T cells. These findings provide a rationale for further investigation of sCD137 as a treatment for T1D and other T cell-mediated autoimmune diseases.
Author List
Itoh A, Ortiz L, Kachapati K, Wu Y, Adams D, Bednar K, Mukherjee S, Chougnet C, Mittler RS, Chen YG, Dolan L, Ridgway WMAuthor
Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCD4-Positive T-Lymphocytes
Cell Cycle
Clonal Anergy
Cytokines
Diabetes Mellitus, Type 1
Female
Immunologic Memory
Insulin
Insulin-Secreting Cells
Interleukin-2
Lymphocyte Activation
Mechanistic Target of Rapamycin Complex 1
Mice
Mice, Inbred NOD
Signal Transduction
T-Lymphocyte Subsets
Tumor Necrosis Factor Receptor Superfamily, Member 9
