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Front Immunol. 2019 Nov 7;10:2566. doi: 10.3389/fimmu.2019.02566. eCollection 2019.

Soluble CD137 Ameliorates Acute Type 1 Diabetes by Inducing T Cell Anergy.

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Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
Department of Surgery, Emory University, Atlanta, GA, United States.
Emory Vaccine Center, Atlanta, GA, United States.
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, United States.
Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.


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.


T cell anergy; T cells; autoimmunity; soluble CD137; type 1 diabetes

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