Both soluble and cell surface CD137 expressed by Foxp3+ CD4 T cells restrain autoimmune diabetes

Rabia Nabi; Chien-Wei Lin; Yu Wang; Ashley E Ciecko; Bardees M Foda; Yushu Wang; Amber Drewek; Scott M Lieberman; William M Ridgway; Yi-Guang Chen

doi:10.1084/jem.20252647

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Both soluble and cell surface CD137 expressed by Foxp3+ CD4 T cells restrain autoimmune diabetes

Journal article

Open access

Peer reviewed

Both soluble and cell surface CD137 expressed by Foxp3+ CD4 T cells restrain autoimmune diabetes

Rabia Nabi, Chien-Wei Lin, Yu Wang, Ashley E Ciecko, Bardees M Foda, Yushu Wang, Amber Drewek, Scott M Lieberman, William M Ridgway and Yi-Guang Chen

The Journal of experimental medicine, Vol.223(8), e20252647

08/03/2026

DOI: 10.1084/jem.20252647

PMID: 42412561

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Abstract

CD137 is expressed in a subset of Foxp3+ regulatory CD4 T cells (Tregs), but its immunoregulatory role is not fully defined. Due to alternative splicing that removes the transmembrane domain-encoding exon, CD137 exists in both membrane and soluble forms. We investigated the function of CD137 in Foxp3+ Tregs using the NOD mouse model of type 1 diabetes (T1D). Foxp3+ Treg-specific deletion of CD137 reduced circulating soluble CD137 and accelerated T1D development, driven by heightened clonal expansion and differentiation of effector T cells in pancreatic islets. CD137 deficiency in Foxp3+ Tregs reduced their frequency in islets and impaired their differentiation toward a suppressive phenotype. Restoring soluble CD137 in Foxp3+ Tregs lacking its membrane form reduced islet T cell activation and mitigated T1D acceleration without altering the accumulation of suppressive Foxp3+ Tregs. Our results indicate that both soluble and membrane forms of CD137 expressed by Foxp3+ Tregs are critical for immunoregulation, and they independently restrain T1D development.

Animals

CD4-Positive T-Lymphocytes - immunology

Diabetes Mellitus, Type 1 - immunology

Diabetes Mellitus, Type 1 - metabolism

Female

Forkhead Transcription Factors - metabolism

Islets of Langerhans - immunology

Lymphocyte Activation

Mice

Mice, Inbred NOD

T-Lymphocytes, Regulatory - immunology

T-Lymphocytes, Regulatory - metabolism

Tumor Necrosis Factor Receptor Superfamily, Member 9 - genetics

Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology

Tumor Necrosis Factor Receptor Superfamily, Member 9 - metabolism

Details

Title: Subtitle: Both soluble and cell surface CD137 expressed by Foxp3+ CD4 T cells restrain autoimmune diabetes
Creators: Rabia Nabi - Medical College of Wisconsin
Chien-Wei Lin - Medical College of Wisconsin
Yu Wang - Medical College of Wisconsin
Ashley E Ciecko - Medical College of Wisconsin
Bardees M Foda - Medical College of Wisconsin
Yushu Wang - Medical College of Wisconsin
Amber Drewek - Medical College of Wisconsin
Scott M Lieberman - University of Iowa
William M Ridgway - University of California, Davis
Yi-Guang Chen - Medical College of Wisconsin
Resource Type: Journal article
Publication Details: The Journal of experimental medicine, Vol.223(8), e20252647
DOI: 10.1084/jem.20252647
PMID: 42412561
ISSN: 0022-1007
eISSN: 1540-9538
Publisher: Rockefeller University Press
Grant note: DK107541 / NIH HHS DK121747 / NIH HHS
Language: English
Date published: 08/03/2026
Academic Unit: Stead Family Department of Pediatrics; Rheumatology, Allergy, and Immunology
Record Identifier: 9985180877902771

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