The ADAP-TRIM21-ZEB2 axis regulates CD8⁺ T cell effector expansion and central memory-like differentiation

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• The ADAP-SKAP1 module is crucial for T cell receptor (TCR) signaling and adhesion.
• The precise role of ADAP in CD8+ T cell differentiation is not fully understood.

Purpose of the Study:

• To investigate the function of ADAP in CD8+ T cell differentiation during viral infection.
• To elucidate the molecular mechanisms by which ADAP regulates T cell fate.

Main Methods:

• Utilized a mouse model of acute lymphocytic choriomeningitis virus (LCMV) infection.
• Performed RNA sequencing (RNA-seq) to analyze gene expression changes in ADAP-deficient T cells.
• Investigated protein-protein interactions and ubiquitination assays to determine molecular mechanisms.

Main Results:

• ADAP deficiency enhanced CD8+ T cell effector expansion and function, including increased IFN-γ and granzyme B production.
• ADAP-deficient CD8+ T cells showed a greater propensity for central memory T cell formation (CD44Hi CD62LHi).
• ZEB2 was identified as a key transcription factor upregulated in ADAP-deficient T cells; ADAP, via TRIM21, promotes ZEB2 degradation.

Conclusions:

• ADAP acts as a negative regulator of CD8+ T cell responses during viral infection.
• A novel ADAP-TRIM21-ZEB2 signaling axis controls CD8+ T cell differentiation.
• This pathway offers new insights into the regulation of T cell fate decisions.