CELL SURFACE RECEPTORS ON CYTOTOXIC T CELLS

细胞毒性 T 细胞上的细胞表面受体

• 批准号: 6124161
• 负责人: CORNELIS P TERHORST
• 金额: $ 23.98万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-08-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6124161
• 关键词: CD3 molecule; T cell receptor; biological signal transduction; calcineurin; cytotoxic T lymphocyte; guanine nucleotide binding protein; laboratory mouse; laboratory rabbit; leukocyte activation /transformation; mitogen activated protein kinase; phosphatidylinositol 3 kinase; protein kinase C; tissue /cell culture; transfection; yeast two hybrid system

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.

作为对抗原识别的反应，静止的T淋巴细胞经历了一种复合体 一系列称为T细胞激活的事件，启动信号 诱导T细胞增殖、活化的信号转导途径 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/CD3)信号不足以控制细胞的激活 静息T细胞：通过例如CD4/8的共刺激信号， 需要提供CD28/CTLA4。尽管人们已经了解了很多关于 T细胞激活，一系列有序的分子事件参与 整个过程还有待确定。紧跟在T细胞之后 CD3蛋白募集非受体蛋白酪氨酸的抗原识别 磷酸化CD3免疫受体酪氨酸激活基序的激酶 (ITAMS)。可能随之而来的四条主要途径 CD3ITAM的酪氨酸磷酸化是：MAP-K通路， 钙调神经磷酸酶途径、PKC和PI3‘-激酶途径。我们会集中精力 我们在CD3-Zeta和CD3-Zeta偶联的生化反应方面的努力 CD3-epsilon到MAP激酶通路。对早期的监管 从CD3-epsilon和CD3-Zeta到RAS和Rho的生化步骤 家族GTP结合蛋白似乎在精确控制中起关键作用 T细胞的激活。我们的一般假设是，大多数 调节对抗原的反应性的生化事件是最近的 CD3蛋白。具体来说，我们建议： -分析CD3-Zeta或CD3-的初始生化步骤- Epsilon以RAS激活MAP激酶Raf-1。 -检验14.3.3/CD3-Zeta复合体提供 CD3-Zeta和Raf之间的一些通路的脚手架 已启动。 -测试Rho家族GTP结合蛋白与 CD3-Zeta激活MAP-Kinase JNK和p38。 -进一步研究外周血中TCR信号转导 CD3-Zeta/ETA缺失小鼠的CD8+T淋巴细胞。