Role of ADAM10 and ADAM17 in Regulating CD137 Function

Area of Science:

• Immunology
• Molecular Biology
• Biochemistry

Background:

• Human CD137 (4-1BB) and its ligand CD137L (4-1BBL) are key immune regulators involved in inflammation, autoimmunity, and oncology.
• Elevated soluble CD137 (sCD137) levels are observed in rheumatoid arthritis and malignancies, previously thought to be a splice variant.
• CD137/CD137L interactions mediate crucial bidirectional cellular responses.

Purpose of the Study:

• To investigate the mechanism of soluble CD137 (sCD137) generation.
• To elucidate the role of specific enzymes and cellular components in sCD137 release.
• To understand the functional implications of sCD137 in immune responses and potential therapeutic strategies.

Main Methods:

• Utilized transfected cell lines and primary T cells to study CD137 shedding.
• Employed ADAM10 inhibition to assess its role in sCD137 generation.
• Investigated the influence of phosphatidylserine (PS) and the phospholipid scramblase Anoctamin-6 (ANO6) on ADAM10-mediated shedding.

Main Results:

• Demonstrated that A Disintegrin and Metalloproteinase (ADAM)10, and potentially ADAM17, are central to sCD137 generation.
• Showed that ADAM10 inhibition effectively blocked sCD137 release.
• Confirmed that Anoctamin-6 (ANO6) modulates ADAM10 function by trafficking phosphatidylserine, influencing constitutive and stimulated sCD137 shedding, and that sCD137 augments T cell proliferation.

Conclusions:

• Soluble CD137 (sCD137) is generated through enzymatic shedding by ADAM10, not alternative splicing.
• Phosphatidylserine exposure and Anoctamin-6 play critical roles in regulating this shedding process.
• These findings offer new insights into CD137/CD137L immune response regulation and impact immunotherapeutic approaches.