Proximity between immune receptors on the cell surface and the sensitivity of Tce

细胞表面免疫受体的接近程度和 Tce 的敏感性

• 批准号: 7659807
• 负责人: Yuri Sykulev
• 金额: $ 19.03万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659807
• 关键词: Accounting; Affect; Antigens; Binding; Biological; Biosensor; CD8B1 gene; Cell surface; Cells; Cellular Immunity; Complex; Cytotoxic T-Lymphocytes; Data; Detection; Development; Diffuse; Energy Transfer; Fluorescence; Histocompatibility Antigens Class I; Host Defense; Immunologic Receptors; Life; Lymphocyte; MHC Class I Genes; Malignant Neoplasms; Measurement; Measures; Methods; Modeling; Molecular; Patients; Peptide/MHC Complex; Peptides; Performance; Population; Proteins; Publishing; Quantum Dots; Research; Role; Semiconductors; Sensitivity and Specificity; Signal Transduction; Simulate; Spectrum Analysis; Surface; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Time; Virus; Virus Diseases; Work; cancer cell; cytotoxic; experience; fighting; molecular assembly/self assembly; nanocrystal; nanoparticle; novel; public health relevance; receptor; receptor binding; receptor-mediated signaling; research study; response; segregation; spatial relationship; tool

DESCRIPTION (provided by applicant): Several lines of evidence, including our own data, suggest that a fraction of CD8, p56lck- associated protein that marks a population of cytotoxic T lymphocytes (CTL) and binds to the nonpolymorphic domain of MHC class I (MHC-I) molecules, form molecular assemblies with T-cell receptor (TCR) on the CTL surface. The formation of these assemblies facilitates the sensitivity and the specificity of CTL responses against target cells. We and others have shown that MHC proteins on the cell surface are also concentrated in clusters and that disruption of the clusters affects the ability to effectively present peptide antigens to T cells. We have recently simulated MHC clusters with a novel tool, semiconductor nanoparticles, quantum dots (QD), bearing controlled numbers of pMHC complexes, and found that the cognate and non-cognate pMHC complexes on QDs effectively cooperate in the binding of QD/pMHC to live T cells and in the induction of T cell responses. Our working hypothesis is that clustering of immune receptors on the cell surface leads to increased proximity between the receptor molecules that are essential for their ability to cooperate in the induction of downstream receptor-mediated signaling. The hypothesis will be tested by pursuing 2 specific aims: (i) To evaluate the proximity between TCR and CD8 on the surface of naive and antigen experienced CD8+ T cells and to relate changes in the extent of CD8-TCR clustering to the sensitivity and specificity of CTL responses; (ii) To estimate the separation distances between pMHC complexes attached to QDs and to compare them with corresponding distances between MHC proteins on the surface of living cells and to evaluate the impact of the proximity between pMHC with various biological activities bound to QDs on the efficiency of such QD/pMHC biosensors to elicit T cell responses. The proposed experiments are expected to generate sufficient amount of experimental parameters, which then can be utilized for building comprehensive models to explain mechanisms of triggering of the proximal signaling. Understanding the role of separating distances between immune receptors on T cells and target cells should enable us to make progress in understanding molecular mechanisms controlling T cell activation and will ultimately permit manipulation of various T cell activities to influence T cell-mediated immunity. Public Health Relevance: Inasmuch as CD8+ cytotoxic lymphocytes are indispensable component of anti- virus and anti-cancer defense of the host body, bettering understanding of the mechanisms of their actions, which is expected to emerge from the proposed research, will facilitate the development of new strategies to enhance the performance of these lymphocytes and to facilitate the ability of patients to fight viral infections and cancer.

描述（申请人提供）：包括我们自己的数据在内的几种证据，表明CD8，p56LCK-相关蛋白标记了细胞毒性T淋巴细胞（CTL）的种群，并与MHC类别I（MHC-I）分子组成的MHC类别（MHC-I）分类的非层状结构域结合（T）这些组件的形成促进了CTL对靶细胞的敏感性和特异性。我们和其他人表明，细胞表面上的MHC蛋白也集中在簇中，而簇的破坏会影响有效地将肽抗原呈现与T细胞的能力。我们最近使用一种新型工具，半导体纳米颗粒，量子点（QD），具有控制的PMHC复合物数量的MHC簇模拟了MHC簇，并发现同源和非同源PMHC在QD上有效合作，在QD/PMHC的结合中有效合作QD/PMHC与T细胞的结合和T细胞诱导的诱导。我们的工作假设是，在细胞表面上的免疫受体聚类会导致受体分子之间的接近度增加，这对于它们在诱导下游受体介导的信号传导中合作的能力至关重要。该假设将通过追求2个特定目的来检验：（i）评估幼稚和抗原表面上TCR和CD8之间经历的CD8+ T细胞之间的接近性，并将CD8-TCR聚类程度的变化与CTL响应的敏感性和特异性相关联； （ii）估计附着在QD上的PMHC复合物之间的分离距离，并将它们与Live细胞表面上MHC蛋白之间的相应距离进行比较，并评估PMHC之间的接近性与QD的各种生物学活性对此类QD/PMHC生物传感器对ELIFIC TERICTICT CYLICIIT TOMIFIIT TOMIFICT CYLICIS TOMIFIC TOMIFIC TOMIFIC TOMIFIC TOMIFIC TOMIFIC TOMIFIC TOMIFIC TOMIFIC TOMIFIC TOMIFIC TOMICTICTICIS TOM的影响。提出的实验有望产生足够数量的实验参数，然后可以用于构建综合模型来解释触发近端信号传导的机制。了解T细胞和靶细胞上免疫受体之间分离距离的作用应使我们能够在理解控制T细胞激活的分子机制方面取得进展，并最终允许操纵各种T细胞活性以影响T细胞介导的免疫。公共卫生相关性：与CD8+细胞毒性淋巴细胞是抗病毒和对宿主身体防御的必不可少的组成部分，可以改善人们对其行为机制的理解，这将从拟议的研究中出现，这将促进对患者的发展效力，以促进这些病毒和癌症的表现，以促进癌症和癌症的表现。