The cell and molecular mechanisms underlying CD28 costimulation

CD28共刺激的细胞和分子机制

基本信息

批准号：
9968771
负责人：
ARTHUR WEISS
金额：
$ 40.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-08 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9968771
关键词：
1-Phosphatidylinositol 3-Kinase Actins Adhesions Affect Antigen-Presenting Cells Antigens Autoimmunity Awareness Biochemical Biology CD28 Antigens CD28 gene CD3 Antigens CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD80 gene CD86 gene CD8B1 gene Cell Communication Cell surface Cells Chemicals Clinical Collaborations Cytoplasmic Tail Cytoskeleton Data Dendritic Cells Development Elements Ensure Genetic Hydrolysis Immobilization Immune response Immune system Infection Innate Immune System Interleukin-2 Interruption Lead Ligands Malignant Neoplasms Mature T-Lymphocyte Mediating Modeling Molecular Monoclonal Antibodies Mus Names PLC gamma1 PTK2 gene Pathologic Pathway interactions Phosphatidylinositol 4,5-Diphosphate Phospholipase C Phosphorylation Phosphotransferases Production Proliferating Protein Tyrosine Kinase Proteins Proteomics Recombinants Regulation Serine/Threonine Phosphorylation Signal Pathway Signal Transduction Site Superantigens T cell response T-Cell Activation T-Cell Proliferation T-Cell Receptor T-Lymphocyte Therapeutic Threonine Phosphorylation Site Transplantation Tyrosine base design filamin inhibitor/antagonist insight intercellular cell adhesion molecule kinase inhibitor mutant novel strategies novel therapeutics pathogen phosphoproteomics polyproline recruit response rho GTP-Binding Proteins small molecule inhibitor src-Family Kinases thymocyte

项目摘要

CD28 is a T cell surface molecule that can provide a second signal, when combined with immobilized TCR ligands, to induce naïve T activation. Costimulation results from the interaction of CD28 with its ligands CD80 (B7.1) and CD86 (B7.2) induced on activated antigen-presenting cells by activation of the innate immune system. We do not have a good molecular understanding of how CD28 mediates its costimulatory signals. Models and experimental evidence have suggested that CD28 either: 1) augments the magnitude of TCR signaling; or, 2) provides a unique signal, qualitatively distinct from that provided by the TCR. It is important to understand the molecular signaling pathways underlying costimulation since interrupting costimulation has been important clinically. A deeper insight into CD28 signaling pathways may enable the development of new therapeutics that would be useful in blocking the immune system. Very recent studies from my lab provide some new insights and suggest approaches and clues that will enable us identify previously unrecognized components of the CD28-regulated signaling pathways and permit a more complete understanding of CD28 signaling. These chemical-biology, genetic and proteomic studies lead us to hypothesize that an important consequence of CD28 costimulation is the regulation of the actin cytoskeleton and this influences signals downstream of the TCR. We will explore this via the following specific aims: 1) Determine the mechanism by which costimulation modulates the actin cytoskeleton to facilitate PLCγ1 mediated hydrolysis of PIP2 in double positive (CD4+CD8+, DP) thymocytes and in more mature T cells; 2) Determine how CD28 overcomes a negative regulatory influence of Pyk2 and Cbl-b on T cell signaling leading to IL-2 production and T cell proliferation; and, 3) Using recently obtained phosphoproteomic data, we will identify key components of the pathway downstream of CD28 and those that modulate the actin cytoskeleton in response to CD28 costimulation.

CD28 是一种 T 细胞表面分子，与固定化 TCR 结合时可提供第二信号配体，诱导幼稚 T 激活共刺激是 CD28 与其配体 CD80 相互作用的结果。 (B7.1) 和 CD86 (B7.2) 通过先天免疫的激活在激活的抗原呈递细胞上诱导我们对 CD28 如何介导其共刺激信号还没有很好的分子理解。模型和实验证据表明 CD28 可以：1) 增强 TCR 的强度信号；或者，2) 提供与 TCR 提供的质量不同的独特信号。了解共刺激背后的分子信号传导途径，因为中断共刺激已经更深入地了解 CD28 信号通路可能有助于开发新的药物。我的实验室最近的研究提供了有助于阻断免疫系统的疗法。一些新的见解以及建议的方法和线索，使我们能够识别以前未识别的 CD28 调节的信号通路的组成部分，并允许更全面地了解 CD28 这些化学生物学、遗传学和蛋白质组学研究使我们认识到这一点很重要。 CD28 共刺激的结果是肌动蛋白细胞骨架的调节，这会影响我们将通过以下具体目标来探索这一点：1）确定共刺激调节肌动蛋白细胞骨架以促进 PLCγ1 介导的水解的机制双阳性（CD4+CD8+，DP）胸腺细胞和更成熟的 T 细胞中的 PIP2 2) 确定 CD28 的作用；克服了 Pyk2 和 Cbl-b 对导致 IL-2 产生的 T 细胞信号传导的负面调节影响， T 细胞增殖；以及，3) 使用最近获得的磷酸化蛋白质组数据，我们将确定 T 细胞增殖的关键成分 CD28 的下游途径以及响应 CD28 调节肌动蛋白细胞骨架的途径共刺激。