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Original Article

^a Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
^b Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
^c Department of Immunology, Duke Medical Center, Durham, NC 27710
LCMB/NCI/NIH, Bldg. 37, Rm. 1E24, 37 Convent Dr., Bethesda, MD 20892-4255.301-496-8479301-496-8910

connies{at}helix.nih.gov

The integral membrane adapter protein linker for activation of T cells (LAT) performs a critical function in T cell antigen receptor (TCR) signal transduction by coupling the TCR to downstream signaling pathways. After TCR engagement, LAT is tyrosine phosphorylated by ZAP-70 creating docking sites for multiple src homology 2–containing effector proteins. In the Jurkat T cell line, the distal four tyrosines of LAT bind PLC-1, Grb2, and Gads. Mutation of these four tyrosine residues to phenylalanine (4YF) blocked TCR-mediated calcium mobilization, Erk activation, and nuclear factor (NF)-AT activation. In this study, we examined whether these four tyrosine residues were essential for T cell development by generating LAT "knock-in" mutant mice that express the 4YF mutant protein under the control of endogenous LAT regulatory sequences. Significantly, the phenotype of 4YF knock-in mice was identical to LAT^–/– (null) mice; thymocyte development was arrested at the immature CD4^–CD8^– stage and no mature T cells were present. Knock-in mice expressing wild-type LAT protein, generated by a similar strategy, displayed a normal T cell developmental profile. These results demonstrate that the distal four tyrosine residues of LAT are essential for preTCR signaling and T cell development in vivo.

Key Words: thymocyte • development • signal transduction • adapter • gene targeting

© 2001 The Rockefeller University Press

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