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Science 18 December 1998:
Vol. 282. no. 5397, pp. 2263 - 2266
DOI: 10.1126/science.282.5397.2263
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Reports

Molecular Basis of T Cell Inactivation by CTLA-4

Kyung-Mi Lee, * Ellen Chuang, * Matthew Griffin, Roli Khattri, David K. Hong, Weiguo Zhang, David Straus, Lawrence E. Samelson, Craig B. Thompson, Jeffrey A. Bluestone dagger

CTLA-4, a negative regulator of T cell function, was found to associate with the T cell receptor (TCR) complex zeta  chain in primary T cells. The association of TCRzeta with CTLA-4, reconstituted in 293 transfectants, was enhanced by p56lck-induced tyrosine phosphorylation. Coexpression of the CTLA-4-associated tyrosine phosphatase, SHP-2, resulted in dephosphorylation of TCRzeta bound to CTLA-4 and abolished the p56lck-inducible TCRzeta -CTLA-4 interaction. Thus, CTLA-4 inhibits TCR signal transduction by binding to TCRzeta and inhibiting tyrosine phosphorylation after T cell activation. These findings have broad implications for the negative regulation of T cell function and T cell tolerance.

K.-M. Lee, M. Griffin, R. Khattri, D. K. Hong, J. A. Bluestone, Ben May Institute for Cancer Research, and Committee on Immunology, University of Chicago, Chicago, IL 60637, USA. E. Chuang, Committee on Immunology, and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL 60637, USA. W. Zhang and L. E. Samelson, Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. D. Straus, Committee on Immunology, and Department of Pathology and Medicine, University of Chicago, Chicago, IL 60637, USA. C. B. Thompson, Howard Hughes Medical Institute, Ben May Institute for Cancer Research, Committee on Immunology, and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL 60637, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: jbluest{at}immunology.uchicago.edu

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CTLA-4 blockade of antigen-induced cell death.
S. da Rocha Dias and C. E. Rudd (2001)
Blood 97, 1134-1137
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Inhibition of IgG1 and IgE Production by Stimulation of the B Cell CTLA-4 Receptor.
C. Pioli, L. Gatta, V. Ubaldi, and G. Doria (2000)
J. Immunol. 165, 5530-5536
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Structure of Murine CTLA-4 and Its Role in Modulating T Cell Responsiveness.
D. A. Ostrov, W. Shi, J.-C. D. Schwartz, S. C. Almo, and S. G. Nathenson (2000)
Science 290, 816-819
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Pinpointing when T cell costimulatory receptor CTLA-4 must be engaged to dampen diabetogenic T cells.
F. Lühder, C. Chambers, J. P. Allison, C. Benoist, and D. Mathis (2000)
PNAS
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