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Science 296 (5575): 2040-2043

Copyright © 2002 by the American Association for the Advancement of Science

A LAT Mutation That Inhibits T Cell Development Yet Induces Lymphoproliferation

Connie L. Sommers,1 Cheung-Seog Park,2 Jan Lee,3 Chiguang Feng,2 Claudette L. Fuller,1 Alexander Grinberg,2 Jay A. Hildebrand,1 Emanuela Lacaná,3 Rashmi K. Menon,1 Elizabeth W. Shores,3 Lawrence E. Samelson,1 Paul E. Love2*

Mice homozygous for a single tyrosine mutation in LAT (linker for activation of T cells) exhibited an early block in T cell maturation but later developed a polyclonal lymphoproliferative disorder and signs of autoimmune disease. T cell antigen receptor (TCR)-induced activation of phospholipase C-gamma 1 (PLC-gamma 1) and of nuclear factor of activated T cells, calcium influx, interleukin-2 production, and cell death were reduced or abrogated in T cells from LAT mutant mice. In contrast, TCR-induced Erk activation was intact. These results identify a critical role for integrated PLC-gamma 1 and Ras-Erk signaling through LAT in T cell development and homeostasis.

1 Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health,
2 Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
3 Division of Therapeutic Proteins, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
*   To whom correspondence should be addressed. E-mail: pel{at}

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Mutation of the phospholipase C-{gamma}1-binding site of LAT affects both positive and negative thymocyte selection.
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The adaptor molecules LAT and SLP-76 are specifically targeted by Yersinia to inhibit T cell activation.
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J. Exp. Med. 201, 361-371
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Linker for Activation of T Cells Integrates Positive and Negative Signaling in Mast Cells.
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J. Immunol. 173, 5086-5094
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Linker for Activation of B Cells: A Functional Equivalent of a Mutant Linker for Activation of T Cells Deficient in Phospholipase C-{gamma}1 Binding.
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The Importance of Three Membrane-distal Tyrosines in the Adaptor Protein NTAL/LAB.
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Superantigen Stimulation Reveals the Contribution of Lck to Negative Regulation of T Cell Activation.
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J. Immunol. 172, 222-230
   Abstract »    Full Text »    PDF »
The Four Distal Tyrosines Are Required for LAT-dependent Signaling in Fc{varepsilon}RI-mediated Mast Cell Activation.
S.-i. Saitoh, S. Odom, G. Gomez, C. L. Sommers, H. A. Young, J. Rivera, and L. E. Samelson (2003)
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SLAM-associated Protein Deficiency Causes Imbalanced Early Signal Transduction and Blocks Downstream Activation in T Cells from X-linked Lymphoproliferative Disease Patients.
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G. Werlen, B. Hausmann, D. Naeher, and E. Palmer (2003)
Science 299, 1859-1863
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M. Zhu, E. Janssen, and W. Zhang (2003)
J. Immunol. 170, 325-333
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