CELL SURFACE RECEPTORS ON CYTOTOXIC T CELLS

在对抗原识别的应答中，静息T淋巴细胞经历一个复杂的 一系列被称为T细胞激活的事件， 导致T细胞增殖、活化诱导的转导途径 细胞死亡、细胞因子产生或细胞溶解。 然而，T细胞抗原 受体（TCR/CD 3）信号传导不足以控制 静息T细胞：通过例如CD 4/8的共刺激信号， 需要提供CD 28/CTLA 4。 尽管我们已经了解了很多 T细胞活化，一系列有序的分子事件参与了T细胞的活化。 整个过程还有待确定。在T细胞 抗原识别CD 3蛋白募集非受体蛋白酪氨酸 磷酸化CD 3免疫受体酪氨酸激活基序的激酶 （ITAMS）。 四个主要的途径，可能随之而来的 酪氨酸磷酸化的CD 3 ITAM是：MAP-激酶途径， 钙调神经磷酸酶途径、PKC和PI 3 '-激酶途径。 我们将集中 我们在将CD 3-zeta和 CD 3-CD 4与MAP激酶通路的相互作用。 早期监管 从CD 3-CD 4和CD 3-zeta到Ras和Rho的生化步骤 家族GTP结合蛋白似乎在精确控制 T细胞活化的过程。 我们的一般假设是， 调节对抗原的反应性的生物化学事件与 CD 3蛋白质。 具体而言，我们建议： - 分析由CD 3-zeta或CD 3-zeta引起的初始生化步骤， 在MAP激酶Raf-1的激活中，Ras与Rat的结合。 - 检验14.3.3/CD 3-zeta复合物提供了 支架上的CD 3-zeta和Raf之间的一些途径是 启动。 - 检验Rho家族GTP结合蛋白与 CD 3-zeta激活MAP激酶JNK和p38。 - 进一步研究外周CD 4+细胞中的体外TCR信号转导， 和来自CD 3-zeta/eta缺失小鼠的CD 8 + T淋巴细胞。

In response to antigen recognition, resting T lymphocytes undergo a complex series of events known as T-cell activation that initiates signal transduction pathways leading to T cell proliferation, activation induced cell death, cytokine production, or cytolysis. However, T cell antigen receptor (TCR/CD3) signaling is not sufficient to control activation of resting T cells: co-stimulatory signals through for instance CD4/8, CD28/CTLA4 need to be provided. Although much has been learned about T-cell activation, an orderly array of the molecular events involved in the whole process remains to be established. Immediately following T-cell antigen recognition the CD3 proteins recruit non-receptor-protein-tyrosine kinases to phosphorylate the CD3 Immunerceptor Tyrosine Activation Motifs (ITAMS). The four principal pathways that potentially ensue upon tyrosinephosphorylation of the CD3 ITAMs are: the MAP-kinase pathways, the Calcineurin pathway, a PKC and a PI3'-kinase pathway. We will concentrate our efforts on the biochemical reactions which couple CD3-zeta and CD3-epsilon to the MAP kinase pathways. Regulation of the early biochemical steps from CD3-epsilon and CD3-zeta towards Ras and the Rho family GTP binding proteins appear to be critical in the precise control of T cell activation. Our general hypothesis is that most of the biochemical events that regulate responsiveness to antigens are proximal to the CD3 proteins. Specifically we propose to: -Analyze the initial biochemical steps leading from CD3-zeta or CD3- epsilon to Ras in the activation of the MAP kinase Raf-1. -Test the hypothesis that the 14.3.3/CD3-zeta complex provides a scaffold upon which some of the pathways between CD3-zeta and Raf are initiated. -Test the hypothesis that a Rho family GTP binding protein complexes with CD3-zeta to activate the MAP-kinases JNK and p38. -Further study the in vitro TCR signal transduction in peripheral CD4 plus and CD8 plus T lymphocytes from CD3-zeta/eta null mice.