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J. Exp. Med.,
Volume 187, Number 10, May 18, 1998 1721-1727
By
From the * Department of Pathology, University of Massachusetts Medical Center, Worcester,
Massachusetts 01655; the 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 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
/
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 
1 tyrosine
phosphorylation are substantially reduced in Itk/ T cells. In contrast, TCR-
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.
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