Protein tyrosine kinase p56lck controls allelic exclusion of T-cell receptor beta-chain genes

Abstract

During T-cell development, site-specific DNA rearrangements mediating assembly of beta- and alpha-chain genes of the T-cell receptor (TCR) are developmentally ordered. In particular, assembly and expression of a complete beta-chain gene blocks further rearrangements at the beta-locus (a process referred to as allelic exclusion) and drives the generation and expansion of CD4+8+ cells. Although the mechanism used by TCR beta chains to deliver such signals is unknown, studies in transgenic animals have suggested that the lymphocyte-specific protein tyrosine kinase p56lck may impinge on a similar signalling pathway. The hypothesis that TCR beta chains deliver intracellular signals via p56lck makes an explicit prediction: that interference with p56lck function will mitigate the effects of a simultaneously expressed TCR beta chain. Here we confirm this prediction through examination of allelic exclusion in mice expressing both a functional TCR beta chain transgene and a catalytically inactive form of p56lck.