The cell and molecular mechanisms underlying CD28 costimulation

CD28共刺激的细胞和分子机制

• 批准号: 10308437
• 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
• 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/10308437
• 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; 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

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 系统。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 信号发送；或者，2) 提供独特的信号，其质量不同于 TCR 提供的信号。重要的是 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 临床上具有重要意义。更深入地了解 CD28 信号通路可能有助于开发新的 有助于阻断​​免疫系统的疗法。我的实验室最近的研究提供了 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 发信号。这些化学生物学、遗传学和蛋白质组学研究使我们推测，一个重要的 CD28 共刺激的结果是肌动蛋白细胞骨架的调节，这会影响 TCR 下游的信号。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如何 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； 3）利用最近获得的磷酸化蛋白质组数据，我们将确定 CD28 下游的通路以及响应 CD28 调节肌动蛋白细胞骨架的通路 共刺激。