title: Regulation of T cell receptor signaling by activation-induced zinc influx.
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. Temporal or spatial changes in bioavailable zinc may influence the activity of several enzymes, including kinases and phosphatases. We provide evidence that zinc functions as an ionic signaling molecule after T cell activation. Cytoplasmic zinc concentrations increased within 1 min after T cell receptor (TCR) triggering, in particular in the subsynaptic compartment. The increase depended on the extracellular zinc concentrations and was inhibited by silencing zinc transporter Zip6. Increased zinc influx reduced the recruitment of SHP-1 to the TCR activation complex, augmented ZAP70 phosphorylation and sustained calcium influx. By calibrating TCR activation thresholds, increased extracellular zinc bioavailability facilitated the induction of T cell proliferative responses to suboptimal stimuli.
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Mingcan
authors.initials: M
authors.lastname: Yu
authors.forename: Won-Woo
authors.initials: WW
authors.lastname: Lee
authors.forename: Deepak
authors.initials: D
authors.lastname: Tomar
authors.forename: Sergey
authors.initials: S
authors.lastname: Pryshchep
authors.forename: Marta
authors.initials: M
authors.lastname: Czesnikiewicz-Guzik
authors.forename: David L
authors.initials: DL
authors.lastname: Lamar
authors.forename: Guangjin
authors.initials: G
authors.lastname: Li
authors.forename: Karnail
authors.initials: K
authors.lastname: Singh
authors.forename: Lu
authors.initials: L
authors.lastname: Tian
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
mesh_terms: D000328:Adult; D000081247:CSK Tyrosine-Protein Kinase; D027682:Cation Transport Proteins / Q000502:physiology; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000502:physiology; D015032:Zinc / Q000378:metabolism*; D019061:src-Family Kinases
chemical_list: D027682:Cation Transport Proteins; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; C530151:SLC39A8 protein, human; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D019061:src-Family Kinases; C000631346:CSK protein, human; D015032:Zinc