TRANSMEMBRANE SIGNALING BY CD4 IN T-HELPER CELLS

CD 4 + T辅助淋巴细胞（Th）与特异性抗原的相互作用- 呈递细胞（APC）导致细胞因子的分泌， 增殖 除了它们的自分泌作用，许多细胞因子 还影响产生抗体的B淋巴细胞的生长和成熟 和细胞毒性T淋巴细胞。 Th细胞，因此，发挥中央调节 在宿主对抗原的免疫应答中的作用。 述抗原特异性T 细胞受体（TCR）决定抗原肽的识别，但非TCR决定抗原肽的识别。 特异性辅助蛋白也促进与APC的结合。 的cd 4 分子通过与Th-APC的相互作用参与Th-APC粘附。 单形决定簇对APC携带的II类蛋白质。 最近 研究表明，几种T细胞辅助蛋白通常在 相对“非活性”状态，但变得活化，以结合其配体 通过TCR接合。 初步结果表明，这也是 CD 4-II类结合的病例。 该提案的一个目的是雇用 纯化的II类蛋白质，以进一步阐明事件控制 CD 4 II类蛋白之间的TCR活化结合。 在Th细胞上启动几个跨膜信号传导事件 通过特异性APC激活;这些包括酪氨酸激酶的激活 和磷脂酰肌醇途径，这导致增加 细胞内游离Ca ~（2+）和活化蛋白激酶浓度 C. CD 4分子在Th细胞跨膜过程中起着直接的作用 信号传导，如通过其细胞内与 酪氨酸激酶p56 lck。 因此，将进行实验， 识别那些信号事件，具体涉及 活化CD 4以结合II类蛋白，以及由 结合，这可能有助于功能反应。 最后的目的是提出实验，以确定定性和 附加辅助相互作用的定量效应，例如 通过LFA 1和VLA受体介导的TCR和CD 4依赖性结合 和信号事件。 因此，拟议的实验应 有助于我们理解T 淋巴细胞识别并启动对抗原的功能性应答 APC的。

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.