Journal of Leukocyte Biology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
QUICK SEARCH:   [advanced]


     

A more recent version of this article appeared on December 1, 2003

Published online before print September 12, 2003
This Article
Right arrow Full Text (Reprint (PDF))
Right arrow All Versions of this Article:
jlb.0503198v1
74/6/1102    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Siu, E.
Right arrow Articles by Madrenas, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Siu, E.
Right arrow Articles by Madrenas, J.
© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0503198

Received for publication May 5, 2003.
Revised July 16, 2003.
Accepted for publication August 12, 2003.

Article

TCR subunit specificity of CTLA-4-mediated signaling

Eric Siu *, Beatriz M. Carreno {dagger}, and Joaquín Madrenas *@

*The FOCIS Centre for Clinical Immunology and Immunotherapeutics, Robarts Research Institute, and The University of Western Ontario, London, Canada; and {dagger}Wyeth Research, Cambridge, Massachusetts

@ To whom correspondence should be addressed. E-mail: madrenas{at}robarts.ca.


  Abstract

Cytotoxic T-lymphocyte-associated antigen (CTLA)-4 is an activation-induced receptor that down-regulates T cell responses by antagonizing B7-dependent costimulation and/or by transducing a negative signal. The mechanism of CTLA-4-mediated negative signaling is unknown. Recently, it has been postulated that CTLA-4 inhibits T cell activation by causing specific dephosphorylation of the T cell receptor (TCR)-{zeta} chain of the antigen-receptor complex through an lck-dependent recruitment of the Src homology-2-containing tyrosine phosphatase-2. To test this hypothesis, we generated stably transfected T cell clones expressing doxycycline-inducible CTLA-4 with CD25:TCR-{zeta} (CD25-{zeta}) or CD25:CD3-{varepsilon} (CD25-{varepsilon}) fusion proteins. In these clones, ligation of CD25-{zeta} or of CD25-{varepsilon} with antibodies against CD25 induced full T cell activation, as illustrated by extracellular-regulated kinase (ERK) activation and interleukin (IL)-2 production. More importantly, coligation of CTLA-4 with CD25-{zeta} or of CTLA-4 with CD25-{varepsilon} in the respectively transfected clones inhibited ERK activation and IL-2 production, demonstrating that CTLA-4 does not specifically inhibit signals from TCR-{zeta} but can also inhibit signals from CD3-{varepsilon}. Our results suggest that the target specificity of CTLA-4 is determined by its coligation with any given transmembrane receptor rather than by its intracellular mediators.

Key Words: SHP-2 • ERK • interleukin-2




This article has been cited by other articles:


Home page
 J. Immunol.Home page
P. J. Darlington, M. G. Kirchhof, G. Criado, J. Sondhi, and J. Madrenas
Hierarchical Regulation of CTLA-4 Dimer-Based Lattice Formation and Its Biological Relevance for T Cell Inactivation
J. Immunol., July 15, 2005; 175(2): 996 - 1004.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Copyright © 2003 by the Society for Leukocyte Biology.