Spatial coordination of CD28 and TCR signaling

CD28 和 TCR 信号传导的空间协调

• 批准号: 8261369
• 负责人: Lance C Kam
• 金额: $ 32.51万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8261369
• 关键词: Accounting; Antibodies; Behavior; CD28 gene; CD3 Antigens; CD4 Positive T Lymphocytes; CD80 gene; Cell model; Cell physiology; Cells; Communication; Complex; Engineering; Exhibits; Foundations; Goals; Human; Immune; Immune system; Interleukin-2; Language; Lead; Ligands; Lipid Bilayers; Measures; Methods; Microscopy; Modeling; Molecular; Morphologic artifacts; Motion; Mus; PDPK1 gene; Pathway Analysis; Pathway interactions; Pattern; Peptide/MHC Complex; Peptides; Phosphorylation; Play; Positioning Attribute; Process; Proteins; Resolution; Role; Signal Pathway; Signal Transduction; Structure; Surface; Synapses; System; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; base; design; improved; insight; nanometer; nanoscale; public health relevance; receptor; research study; response; segregation; tool

DESCRIPTION (provided by applicant): T cell costimulation plays a vital role in coordinating both long- and short-term responsiveness of the adaptive immune system. An emerging picture of this process is that the spatial organization of costimulatory signaling complexes within the immune synapse has a major influence on subsequent cell activation. To directly test this concept, we introduced a system based on a planar substrate that presents multiple ligands to the T cell TCR, CD28, and LFA-1 receptors, thereby directing the organization of this artificial model of the immune synapse. With this platform we previously demonstrated that CD4+ T cells are sensitive to microscale changes in the organization of these signals, as measured by secretion of IL-2, and that mouse and human cells exhibit very different responses to these patterns. The proposed study seeks to use this platform to identify specific molecular processes that coordinate TCR and CD28 signaling, particularly with regards to how the spatial organization of these complexes influences this crosstalk. We also introduce the use of multicomponent supported lipid bilayer systems to explore the nanoscale organization of these interfaces. We focus specifically on PKC8 and Lck as two recognized molecules at the junction of these pathways, and seek to define how the biophysical behaviors of these proteins within the cell influence overall network function. We use the mouse and human cell models as two extreme examples of the overall response, in an effort to identify how the distribution, mobility, and directed motion of these molecules, in response to different organizations of TCR and CD28 signaling, influence traditional cell signaling concepts, such as phosphorylation. Successful completion of these studies will directly provide new insight into how PKC8 and Lck coordinate T cell costimulation. The methods we introduce are widely applicable, and will directly impact the study of signaling in a wide range of cellular systems. PUBLIC HEALTH RELEVANCE: T cell costimulation is a central process of the adaptive immune system coordinating both long- and short- term responsiveness, and understanding of the underlying processes has wide impact in the design of immune-based therapies. This project applies microscale surface engineering approaches to improve understanding of the interaction between signaling pathways associated with T cell costimulation, developing the foundation for models that take into account the spatial organization of cell-cell interfaces. These studies provide new tools dissecting such pathways, and may lead to improved system for directing the activation of T cells for therapeutic applications.

描述（由申请人提供）：T 细胞共刺激在协调适应性免疫系统的长期和短期反应中发挥着至关重要的作用。这一过程的一个新的景象是，免疫突触内共刺激信号复合物的空间组织对随后的细胞激活具有重大影响。为了直接测试这个概念，我们引入了一个基于平面基底的系统，该系统向 T 细胞 TCR、CD28 和 LFA-1 受体提供多个配体，从而指导这种免疫突触人工模型的组织。通过这个平台，我们之前证明了 CD4+ T 细胞对这些信号组织中的微观变化敏感（通过 IL-2 的分泌来测量），并且小鼠和人类细胞对这些模式表现出非常不同的反应。拟议的研究旨在利用该平台来识别协调 TCR 和 CD28 信号传导的特定分子过程，特别是这些复合物的空间组织如何影响这种串扰。我们还介绍了使用多组分支持的脂质双层系统来探索这些界面的纳米级组织。我们特别关注 PKC8 和 Lck 作为这些通路连接处的两个公认分子，并试图定义细胞内这些蛋白质的生物物理行为如何影响整体网络功能。我们使用小鼠和人类细胞模型作为整体响应的两个极端例子，试图确定这些分子的分布、移动性和定向运动如何响应不同的 TCR 和 CD28 信号传导组织，影响传统的细胞信号传导概念，例如磷酸化。这些研究的成功完成将直接为 PKC8 和 Lck 如何协调 T 细胞共刺激提供新的见解。我们介绍的方法具有广泛的适用性，并将直接影响各种细胞系统中信号传导的研究。 公共健康相关性：T 细胞共刺激是适应性免疫系统协调长期和短期反应的核心过程，了解潜在过程对免疫疗法的设计具有广泛影响。该项目应用微尺度表面工程方法来提高对与 T 细胞共刺激相关的信号通路之间相互作用的理解，为考虑细胞-细胞界面空间组织的模型奠定基础。这些研究提供了剖析此类途径的新工具，并可能导致改进用于指导 T 细胞激活以用于治疗应用的系统。