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Originally published online as doi:10.1189/jlb.0503198 on September 12, 2003

Published online before print September 12, 2003
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(Journal of Leukocyte Biology. 2003;74:1102-1107.)
© 2003 by Society for Leukocyte Biology

TCR subunit specificity of CTLA-4-mediated signaling

Eric Siu*, Beatriz M. Carreno{dagger} and Joaquín Madrenas*,1

* 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

1 Correspondence: Robarts Research Institute, P.O. Box 5015, 100 Perth Drive, London, Ontario, Canada N6A 5K8. E-mail: madrenas{at}robarts.ca

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 signal-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 • CTLA-4 • costimulation • T cell activation




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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]


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