USP12 promotes CD4⁺ T cell responses through deubiquitinating and stabilizing BCL10

Area of Science:

• Immunology
• Molecular Biology
• Biochemistry

Background:

• Deubiquitinases (DUBs) are key regulators of biological processes, yet their roles in adaptive immunity are not fully understood.
• Identifying novel DUBs involved in immune cell function is critical for understanding immune responses and developing targeted therapies.

Purpose of the Study:

• To investigate the role of ubiquitin-specific peptidase 12 (USP12) in CD4+ T cell activation and function.
• To elucidate the molecular mechanism by which USP12 regulates T cell responses.
• To assess the therapeutic potential of targeting USP12 in autoimmune diseases and bacterial infections.

Main Methods:

• Utilized genetic manipulation to create USP12-deficient CD4+ T cells.
• Assessed CD4+ T cell activation, differentiation, and proliferation phenotypes.
• Investigated the effect of USP12 deficiency on autoimmune disease models and bacterial infection responses.
• Analyzed the stabilization of B cell lymphoma/leukemia 10 (BCL10) and NF-κB pathway activation via USP12-mediated deubiquitination.

Main Results:

• USP12 was identified as a critical regulator of CD4+ T cell activation, differentiation, and proliferation.
• USP12-deficient CD4+ T cells conferred protection against autoimmune diseases but impaired responses to bacterial infection.
• USP12 stabilizes BCL10 through deubiquitination, leading to NF-κB pathway activation, specifically in CD4+ T cells.
• This regulatory mechanism was specific to CD4+ T cells and not observed in CD8+ T cells.

Conclusions:

• USP12 plays a significant role in CD4+ T cell signaling and immune responses.
• Targeting USP12 presents a potential therapeutic strategy for managing inflammatory conditions and infectious diseases.
• USP12's distinct role in CD4+ T cells highlights its specific therapeutic potential in adaptive immunity.