Defective T-cell receptor signalling 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 lymphocytes bearing highly diverse, but self-tolerant, repertoires of antigen receptors. These processes are initiated when engagement of growth-factor receptors, or the T and B lymphocyte antigen receptors, induces tyrosine phosphorylation of specific SH2- and SH3-domain-containing cytoplasmic proteins, including Vav. Here we show that vav-/- embryonic stem cells generate only limited numbers of immature and mature T and B lymphocytes in the RAG-2 blastocyst complementation assay. Furthermore, Vav-deficient T lymphocytes showed severely impaired antigen receptor signalling. Finally, we demonstrate that Vav-dependent signalling pathways regulate maturation, but not CD4/CD8 lineage commitment, during T-cell-receptor-mediated positive selection of immature CD4+ CD8+ precursors into mature CD4+ CD8- or CD4- CD8+ T cells.
Fischer
K D
KD
Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Zmuldzinas
A
A
Gardner
S
S
Barbacid
M
M
Bernstein
A
A
Guidos
C
C
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000378:metabolism; D001854:Bone Marrow Cells; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D002678:Chimera; D004268:DNA-Binding Proteins; D051379:Mice; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology
D015704:CD4 Antigens; D016827:CD8 Antigens; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; C499308:Rag2 protein, mouse; D011948:Receptors, Antigen, T-Cell; C064655:V(D)J recombination activating protein 2; C496619:Vav1 protein, mouse