Basic residues in the T-cell receptor ζ cytoplasmic domain mediate membrane association and modulate signaling

The T-cell receptor (TCR) consists of a TCR alpha beta heterodimer, a TCR zeta homodimer, and CD3 gamma epsilon and CD3 delta epsilon heterodimers. The precise mechanism of T-cell triggering following TCR ligand engagement remains elusive. Previous studies reported that the cytoplasmic tail of CD3 epsilon binds to the plasma membrane through a basic residuerich stretch (BRS), and proposed that dissociation from the membrane is required for phosphorylation thereof. In this report we show that BRS motifs within the cytoplasmic tail of TCR zeta mediate association with the plasma membrane, and that TCR engagement results in TCR zeta dissociation from the membrane. This dissociation requires phosphorylation of the TCR zeta immunoreceptor tyrosine-based activation motifs by lymphocyte cell-specific protein tyrosine kinase (Lck) but not zeta-chain-associated protein kinase 70 binding. Mutations of the TCR zeta BRS motifs that disrupt this membrane association attenuate proximal and distal responses induced by TCR engagement. These mutations appear to alter the localization of TCR zeta with respect to Lck as well as the mobility of the TCR complex. This study reveals that tyrosine phosphorylation of the TCR zeta cytoplasmic domain regulates its association with the plasma membrane and highlights the functional importance of TCR zeta BRS motifs.