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T-cell receptor signaling is mediated by transient Lck activity, which is inhibited by inorganic mercury

Stamatina E. Ziemba^*, Sherri L. Menard^*, Michael J. McCabe, Jr and Allen J. Rosenspire^*,1

^* Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, Michigan, USA; and

Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA

¹Correspondence: Department of Immunology and Microbiology, 221 Lande Research Bldg., Wayne State University School of Medicine, Detroit, MI 48201, USA. E-mail: arosenspire{at}wayne.edu

Genetically susceptible rodents exposed to low nontoxic levels of inorganic mercury (Hg²⁺) develop idiosyncratic autoimmune disease associated with defective T-cell function. However, the molecular mechanisms underlying this phenomenon remain mostly unexplained. Brief exposure of T cells to micromolar concentrations of Hg²⁺ leads to physiologically relevant nontoxic cellular mercury burdens, and as we have previously reported, attenuates T-cell receptor (TCR) signal strength by 50%. We have found this to be the result of an inadequate activation of the tyrosine kinase ZAP-70, which is hypophosphorylated following TCR stimulation in Hg²⁺ burdened cells when compared to untreated controls. In T cells, ZAP-70 phosphorylation is dependent on lymphocyte-specific protein tyrosine kinase (Lck) activity, which in turn is either positively or negatively regulated by the phosphorylation of specific Lck tyrosine residues. In particular, the general belief is that Lck is negatively regulated by phosphorylation of tyrosine 192 (Y192). We now demonstrate by Western blotting that, in Jurkat T cells, TCR signal transduction (and ZAP-70 phosphorylation) was positively associated with a rapid transient phosphorylation of Y192, which was inhibited in cells that were briefly (5 min) exposed to 5 µM Hg²⁺. Thus, Hg²⁺ inhibits a critical activating role played by Lck Y192 during the most proximal events of the TCR-induced cell signaling.—Ziemba, S. E., Menard, S. L., McCabe, Jr., M. J., Rosenspire, A. J. T-cell receptor signaling is mediated by transient Lck activity, which is inhibited by inorganic mercury.

Key Words: Hg²⁺ • ZAP-70 • lymphocyte • signal transduction