CSK CONTROLS ANTIGEN RECEPTOR-MEDIATED DEVELOPMENT AND SELECTION OF T-LINEAGE CELLS

The development and function of alpha beta T lymphocytes depend on sig nals derived from pre-T and alpha beta T cell receptors (preTCR and al pha beta TCR) (reviewed in refs 1, 2). The engagement of these recepto rs leads to the activation of Lck and Fyn(3,4), which are protein tyro sine kinases (PTKs) of the Src family. It remains unclear to what exte nt the activation of Src-family PTKs can direct the differentiation st eps triggered by preTCR and alpha beta TCR. Here we show that the inac tivation of the negative regulator of Src-family PTKs, carboxy-termina l Src kinase (Csk)(5), in immature thymocytes abrogates the requiremen t for preTCR, alpha beta TCR and major histocompatibility complex (MHC ) class II for the development of CD4(+)8(+) double-positive and CD4() single-positive thymocytes as well as peripheral CD4 alpha beta T-li neage cells. These data show that Csk and its substrates are required to establish preTCR/alpha beta TCR-mediated control over the developme nt of alpha beta T cells.