DEFECTIVE T-CELL RECEPTOR SIGNALING AND POSITIVE SELECTION OF VAV-DEFICIENT CD4(+) CD8(+) THYMOCYTES

DURING lymphocyte development, cellular proliferation and positive and negative selection events ensure the production of T and B lymphocyte s bearing highly diverse, but self-tolerant, repertoires of antigen re ceptors(1,2). These processes are initiated when engagement of growth- factor receptors, or the T-3,T-4 and B-5 lymphocyte antigen receptors, induces tyrosine phosphorylation of specific SH2- and SH3-domain-cont aining cytoplasmic proteins, including Vav(3,6,7). Here we show that v av(-/-) embryonic stern cells generate only limited numbers of immatur e and mature T and B lymphocytes in the RAG-2 blastocyst complementati on assays. Furthermore, Vav-deficient T lymphocytes showed severely im paired antigen receptor signalling. Finally, we demonstrate that Vav-d ependent signalling pathways regulate maturation, but not CD4/ CD8 lin eage commitment, during T-cell-receptor-mediated positive selection of immature CD4(+)CD8(+) precursors into mature CD4(+)CD8(-) or CD4(-)CD 8(+) T cells.