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J. Biol. Chem., Vol. 278, Issue 12, 10150-10156, March 21, 2003
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From the Division of Immunology and Allergy, Department of
Pediatrics, Infection, Immunity, Injury, and Repair Program,
Research Institute, The Hospital for Sick Children and the University
of Toronto, Toronto, Ontario M5G 1X8, Canada
EphB6 is the most recently identified member of
the Eph receptor tyrosine kinase family. EphB6 is primarily expressed
in thymocytes and a subpopulation of T cells, suggesting that it may be
involved in regulation of T lymphocyte differentiation and functions.
We show here that overexpression of EphB6 in Jurkat T cells and
stimulation with the EphB6 ligand, ephrin-B1, results in the selective
inhibition of TCR-mediated activation of JNK but not the MAPK pathway.
EphB6 appears to suppress the JNK pathway by preventing T cell receptor (TCR)-induced activation of the small GTPase Rac1, a critical event in
initiating the JNK cascade. Furthermore, EphB6 blocked anti-CD3-induced
secretion of IL-2 and CD25 expression in a ligand-dependent manner. Dominant negative EphB6 suppressed the inhibitory activity of
the endogenous receptor and enhanced anti-CD3-induced JNK activation, CD25 expression, and IL-2 secretion, confirming the requirement for
EphB6-specific signaling. Activation of the JNK pathway and the
establishment of an IL-2/IL-2R autocrine loop have been shown to play a
role in the negative selection of
CD4+CD8+ self-reacting thymocytes. In
agreement, stimulation of murine thymocytes with ephrin-B1 not only
blocked anti-CD3-induced CD25 up-regulation and IL-2 production, but
also inhibited TCR-mediated apoptosis. Thus, EphB6 may play an
important role in regulating thymocyte differentiation and modulating
responses of mature T cells.
The EphB6 Receptor Inhibits JNK Activation in T Lymphocytes
and Modulates T Cell Receptor-mediated Responses*
,,
*
This work was supported by a grant from the National Cancer
Institute of Canada.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.
Both authors contributed equally to this work.
§
Donald and Audrey Campbell Chair of Immunology. To whom
correspondence should be addressed: Division of Immunology and Allergy, Department of Pediatrics, Infection, Immunity, Injury and Repair Program, The Research Institute of Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Tel.: 416-813-8623; Fax: 416-813-8624; E-mail: chaim.roifman@sickkids.on.ca.
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