Fischer K D, Zmuldzinas A, Gardner S, Barbacid M, Bernstein A, Guidos C
Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Nature. 1995 Mar 30;374(6521):474-7. doi: 10.1038/374474a0.
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.
在淋巴细胞发育过程中，细胞增殖以及阳性和阴性选择事件确保产生带有高度多样化但自我耐受的抗原受体库的T和B淋巴细胞。当生长因子受体或T和B淋巴细胞抗原受体的结合诱导特定含SH2和SH3结构域的细胞质蛋白（包括Vav）的酪氨酸磷酸化时，这些过程就开始了。在这里我们表明，在RAG-2胚泡互补试验中，vav-/-胚胎干细胞仅产生有限数量的未成熟和成熟T和B淋巴细胞。此外，缺乏Vav的T淋巴细胞显示出严重受损的抗原受体信号传导。最后，我们证明，在未成熟的CD4+CD8+前体通过T细胞受体介导的阳性选择成熟为CD4+CD8-或CD4-CD8+T细胞的过程中，Vav依赖性信号通路调节成熟，但不调节CD4/CD8谱系定向。
