TRANSMEMBRANE SIGNALING BY CD4 IN T-HELPER CELLS

CD4+T辅助淋巴细胞(Th)与特异性抗原的相互作用 提呈细胞(APC)导致细胞因子和 扩散。除了自分泌作用外，许多细胞因子 也影响产生抗体的B淋巴细胞的生长和成熟 和细胞毒性T淋巴细胞。因此，TH细胞发挥着中枢调节作用 在宿主对抗原的免疫反应中的作用。抗原特异性T细胞 细胞受体(TCR)决定了抗原肽的识别，但非 特定的辅助蛋白也有助于与APC结合。人类免疫缺陷病毒 分子通过与Th-APC相互作用参与Th-APC的黏附 APC所承载的II类蛋白的单态决定因素。近期 研究表明，几种T细胞辅助蛋白通常存在于 相对不活跃的状态，但被激活以结合它们的配体 通过TCR接洽。初步结果表明，这也是 用于CD4II类结合的案例。这项提议的一个目标是雇用 纯化的II类蛋白以进一步阐明控制事件 TCR激活的CD4II类蛋白之间的结合。 在Th细胞上启动几个跨膜信号事件 由特定的APC激活；其中包括酪氨酸激酶的激活 和磷脂酰肌醇途径，导致增加 细胞内游离钙离子和活化蛋白激酶的浓度 C.CD4分子在Th细胞跨膜中起直接作用 信令，从它与细胞内的关联就可以看出 酪氨酸激酶p56lck。因此，将进行实验，以 确定哪些信令事件具体涉及 激活CD4以结合第II类蛋白，以及由此产生的 结合，这可能有助于功能反应。 最终目的是提出实验，以确定定性和 附加附件交互作用的数量效应，例如 由LFA1和VLA受体介导的TCR和CD4依赖的结合 和信号事件。因此，拟议的实验应该是， 有助于我们理解T细胞的分子机制 淋巴细胞识别并启动对抗原携带的功能性反应 由APC提供。

Interaction of CD4+ T helper lymphocytes (Th) with specific antigen- presenting cells (APC) results in secretion of cytokines and proliferation. In addition to their autocrine effects, many cytokines also effect the growth and maturation of antibody-producing B lymphocytes and cytotoxic T lymphocytes. Th cells, thus, play a central regulatory role in the hosts immune response to antigen. The antigen-specific T cell receptor (TCR) dictates recognition of antigenic peptides, but non- specific accessory proteins also facilitate binding to the APC. The CD4 molecule participates in Th-APC adhesion by its interaction with monomorphic determinants on class II proteins borne by the APC. Recent work has shown that several T cell accessory proteins are normally in a relatively "inactive" state, but become activated to bind their ligands via TCR engagement. Preliminary results suggest that this is also the case for CD4-class II binding. One aim of this proposal is to employ purified class II proteins to further elucidate the events controlling TCR-activated binding between CD4 class II proteins. Several transmembrane signalling events are initiated upon Th cell activation by specific APC; these include activation of tyrosine kinases and the phosphatidylinositol pathway, which results in increased concentrations of intracellular free Ca2+ and activated protein kinase C. The CD4 molecule plays a direct part in Th cell transmembrane signalling, as evidenced by its intracellular association with the tyrosine kinase p56lck. Experiments will, therefore, be performed to identify those signalling events which are specifically involved in the activation of CD4 to bind class II protein, and those resulting from binding, which may contribute to the functional response. The final aim proposes experiments to determine the qualitative and quantitative effect of additional accessory interactions, such as those mediated by LFA1 and the VLA receptors, to TCR- and CD4-dependent binding and signalling events. The proposed experiments should, therefore, contribute to our understanding of the molecular mechanisms by which T lymphocytes recognize and initiate a functional response to antigen borne by APC.