The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/5/1721/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 10, May 18, 1998 1721-1727

Articles

T Cell Receptor–initiated Calcium Release Is Uncoupled from Capacitative Calcium Entry in Itk-deficient T Cells

Karen-Qianye Liu§, Stephen C. Bunnell{ddagger}, Christine B. Gurniak*, and Leslie J. Berg*

From the * Department of Pathology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655; the {ddagger} Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138; and the § Program of Immunology, Division of Medical Sciences, Harvard University, Boston, Massachusetts 02115

Itk, a Tec family tyrosine kinase, plays an important but as yet undefined role in T cell receptor (TCR) signaling. Here we show that T cells from Itk-deficient mice have a TCR-proximal signaling defect, resulting in defective interleukin 2 secretion. Upon TCR stimulation, Itk–/– T cells release normal amounts of calcium from intracellular stores, but fail to open plasma membrane calcium channels. Since thapsigargin-induced store depletion triggers normal calcium entry in Itk–/– T cells, an impaired biochemical link between store depletion and channel opening is unlikely to be responsible for this defect. Biochemical studies indicate that TCR-induced inositol 1,4,5 tris-phosphate (IP3) generation and phospholipase C {gamma}1 tyrosine phosphorylation are substantially reduced in Itk–/– T cells. In contrast, TCR-{zeta} and ZAP-70 are phosphorylated normally, suggesting that Itk functions downstream of, or in parallel to, ZAP-70 to facilitate TCR-induced IP3 production. These findings support a model in which quantitative differences in cytosolic IP3 trigger distinct responses, and in which only high concentrations of IP3 trigger the influx of extracellular calcium.

Key Words: T cell activation • knockout mouse • Tec family tyrosine kinase • calcium flux • T cell receptor signaling

Address correspondence to Leslie J. Berg, Department of Pathology, University of Massachusetts Medical Center, 55 Lake Ave. North, Worcester, MA 01655. Phone: 508-856-8371; Fax: 508-856-8372; E-mail: leslie. berg{at}ummed.edu

Christine Gurniak's current address is Mouse Biology Programme/Monterotondo EMBL, European Molecular Biology Laboratory, Meyerhofstrasse, Postfach 10.2209, 69012 Heidelberg, Germany.

Abbreviations used: ES, embryonic stem; PI3, inositol 1,4,5 tris-phosphate; PLC, phospholipase C.


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