A LAT Mutation That Inhibits T Cell Development Yet Induces Lymphoproliferation

Abstract

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–γ1 (PLC-γ1) 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-γ1 and Ras-Erk signaling through LAT in T cell development and homeostasis.