Control of CD8+ T central memory cell formation via ADAP regulation of TRIM21-mediated ubiquitination of ZEB2

Here, we demonstrated that ADAP deficiency drives CD8+ T-cell polarization toward a central memory phenotype (CD44Hi CD62LHi). During acute lymphocytic choriomeningitis virus (LCMV) Armstrong infection, Adap-/- CD8+ T cells exhibit accelerated effector differentiation, marked by elevated expression of CX3CR1, IFN-γ and granzyme B. Functional analyses revealed that ADAP-deficient CD8+ T cells display heightened cytotoxic capacity in vitro.

RNA sequencing (RNA-seq) further identified ZEB2 as the most significantly upregulated transcription factor in Adap-/- CD8+ T cells. Mechanistically, ADAP interacts with the E3 ubiquitin ligase TRIM21 and positively regulates TRIM21-mediated K48-linked polyubiquitination of ZEB2, thereby impairing its binding to the SMAD3 promoter. Collectively, our findings define an ADAP-TRIM21-ZEB2 axis that governs CD8+ T-cell differentiation plasticity, offering novel insights into therapeutic strategies for modulating T-cell responses.