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

The ADAP (adhesion and degranulation-promoting adapter protein)-SKAP1 signaling module is essential for TCR-mediated activation and LFA-1-dependent adhesion; however, its role in coordinating CD8+ T cell differentiation remains unclear. Here, we show that ADAP acts as a negative regulator of CD8+ T cell response. During acute LCMV-Armstrong infection, ADAP deficiency enhances CD8+ T cell effector expansion and function, as evidenced by increased IFN-γ and granzyme B expression, and subsequently favors the formation of central memory-like CD8+ T cells (CD44Hi CD62LHi). RNA sequencing (RNA-seq) analysis identified ZEB2 as one of the most significantly upregulated transcription factors in Adap -/- CD8+ T cells. Mechanistically, ADAP interacts with the E3 ubiquitin ligase TRIM21 to facilitate K48-linked polyubiquitination and degradation of ZEB2. This, in turn, reduces the binding of ZEB2 to the Smad3 promoter. Collectively, our study identifies a previously uncharacterized ADAP-TRIM21-ZEB2 axis that regulates CD8+ T cell differentiation, providing new mechanistic insights into the control of T cell fate decisions.