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细胞共刺激在协调自适应免疫系统的长期和短期反应性方面起着至关重要的作用。这一过程的新出现的情况是，免疫突触中的共刺激信号传导复合物的空间组织对随后的细胞激活产生了重大影响。为了直接测试这个概念，我们引入了一个基于平面底物的系统，该系统向T细胞TCR，CD28和LFA-1受体呈现多个配体，从而指导了这种免疫突触的人工模型的组织。使用该平台，我们先前证明了CD4+ T细胞对通过IL-2分泌衡量的这些信号组织中的微观变化敏感，并且小鼠和人类细胞对这些模式的响应非常不同。拟议的研究试图使用此平台来确定协调TCR和CD28信号传导的特定分子过程，尤其是关于这些复合物的空间组织如何影响这种串扰的方式。我们还介绍了多组分支持的脂质双层系统的使用来探索这些接口的纳米级组织。我们专门将重点放在PKC8和LCK上，是这些途径连接处的两个公认的分子，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。我们将小鼠和人类细胞模型用作总体反应的两个极端例子，以确定这些分子的分布，活动性和定向运动如何响应TCR和CD28信号的不同组织，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提供有关PKC8和LCK如何协调T细胞共刺激的新见解。我们引入的方法广泛适用，将直接影响广泛的细胞系统中信号的研究。 公共卫生相关性：T细胞共刺激是适应性免疫系统协调长期和短期反应性的中心过程，对基础过程的理解对基于免疫疗法的设计产生了广泛的影响。该项目采用微观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，从而为考虑细胞细胞接口的空间组织的模型奠定了基础。这些研究提供了解剖此类途径的新工具，并可能导致改进的系统，以指导T细胞激活治疗应用。