Regulation of T-cell receptor signaling by activation-induced zinc influx (109.21)

Abstract

Abstract Zinc is a trace element that is essential for innate and adaptive immune responses. In addition to being a structural element of many proteins, zinc also functions as a neurotransmitter and an intracellular messenger. Although cytoplasmic zinc concentrations are strictly controlled, temporal or spatial changes in bioavailable zinc may influence the activity of several enzymes, including kinases and phosphatases. In this study, we provide evidence that zinc functions as an ionic signaling molecule after T-cell activation. Cytoplasmic zinc concentrations increased within one minute after TCR triggering by super antigen presented by myeloid dendritic cells. In contrast to activation-induced calcium influx, increased zinc concentrations were compartmentalized in the subsynaptic area. The zinc increase was dependent on the extracellular zinc concentrations and was inhibited by silencing the plasma membrane zinc transporter Zip6 consistent with influx from extracellular compartments. Increased zinc availability augmented ZAP70 phosphorylation, inhibited SHP-1 recruitment to the T cell signaling complex, slowed down Lck rephosphorylation at position 505 and sustained calcium influx. As a result, increased extracellular zinc bioavailability facilitated the induction of T cell proliferative responses to suboptimal stimuli. We propose that zinc calibrates TCR activation thresholds by inhibiting negative feedback mechanisms in TCR signaling.