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J. Biol. Chem., Vol. 277, Issue 24, 21529-21536, June 14, 2002
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From the Goldyne Savad Institute of Gene Therapy, Hadassah
University Hospital, Jerusalem 91120, Israel
Triggering of the T cell receptor (TCR) leads to
the production of intracellular intermediates with half-life of a few
minutes. Signaling kinetics of events originating from serial TCR
triggering and its relation to antigen dose was investigated. In this
study we documented incremental accumulation of short-lived
intermediates of the extracellular signal-regulated kinase (ERK)
family, produced during successive TCR triggering. The rate and extent
of the intermediate accumulation are essentially determined by the
level of TCR engagement and are augmented by costimulation. ERK-1 and
ERK-2 exhibit different rates of accumulation following serial receptor
triggering. The data indicate that the quantitative kinetic differences
in downstream signaling pathways induce qualitatively distinct
biological outcomes. Although CD69, interleukin-2, and interferon-
Serial Triggering of T Cell Receptors Results in Incremental
Accumulation of Signaling Intermediates*
(IFN-) were primarily produced by high antigen doses that supported
high MAPK phosphorylation, maximal interleukin-5 expression is induced
by low and intermediate stimulus doses that do not support significant
accumulation of activated ERK. We further demonstrated that the rate of
phosphorylated ERK accumulation correlates with the duration of delay
between T cell stimulation and the onset of IFN- response, with
stronger stimuli giving a more rapid IFN- response. This delay might
reflect the time required for the accumulation of signaling
intermediates up to a threshold level that is necessary for activation.
Thus, the data suggest that signaling events originating from
serially triggered TCR are not simply sustained but are gradually
accumulated and are integrated in a corresponding response.
*
This work was supported by the Greensboro Community
Foundation.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed: Goldyne Savad Inst. of
Gene Therapy, Hadassah University Hospital, P. O. Box 12000, Jerusalem 91120, Israel. Tel.: 972-2-6777848; Fax:
972-2-6430982; E-mail: rjacob@hadassah.org.il.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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