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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}helix.nih.gov


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