Knock-in mutation of the distal four tyrosines of linker for activation of T cells blocks murine T cell development.

Journal Article

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 PLCgamma-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.

Full Text

Duke Authors

Cited Authors

  • Sommers, CL; Menon, RK; Grinberg, A; Zhang, W; Samelson, LE; Love, PE

Published Date

  • July 16, 2001

Published In

Volume / Issue

  • 194 / 2

Start / End Page

  • 135 - 142

PubMed ID

  • 11457888

International Standard Serial Number (ISSN)

  • 0022-1007

Language

  • eng

Conference Location

  • United States