The cell and molecular mechanisms underlying CD28 costimulation

CD28共刺激的细胞和分子机制

• 批准号: 9191340
• 负责人: ARTHUR WEISS
• 金额: $ 39.63万
• 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 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9191340
• 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 Proliferation; 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; Phosphorylation Site; Phosphotransferases; Production; Proliferating; Protein Tyrosine Kinase; Proteins; Proteomics; Recombinants; Recruitment Activity; 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; Transplantation; Tyrosine; base; design; filamin; inhibitor/antagonist; insight; intercellular cell adhesion molecule; kinase inhibitor; mutant; novel strategies; novel therapeutics; pathogen; phosphoproteomics; polyproline; public health relevance; response; rho GTP-Binding Proteins; small molecule inhibitor; src-Family Kinases; thymocyte

 DESCRIPTION (provided by applicant): 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.

 描述（由申请人提供）：CD28 是一种 T 细胞表面分子，当与固定化的 TCR 配体结合时，可以提供第二信号，以诱导初始 T 激活。共刺激是由 CD28 与其配体 CD80 (B7.1) 和 CD86 (B7.2) 相互作用引起的，通过先天免疫系统的激活在活化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 信号传导的强度；或者，2) 提供独特的信号，其质量不同于 TCR 提供的信号。了解共刺激背后的分子信号传导途径非常重要，因为中断共刺激在临床上很重要。更深入地了解 CD28 信号通路可能有助于开发可用于阻断免疫系统的新疗法。我实验室最近的研究提供了一些新的见解，并提出了方法和线索，使我们能够识别以前未识别的 CD28 调节信号通路的组成部分，并允许更全面地了解 CD28 信号传导。这些化学生物学、遗传学和蛋白质组学研究使我们假设 CD28 共刺激的一个重要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进行探索：1）确定共刺激调节肌动蛋白细胞骨架以促进双阳性（CD4+CD8+，DP）胸腺细胞和更成熟的T细胞中PLCγ1介导的PIP2水解的机制； 2) 确定CD28如何克服Pyk2和Cbl-b对T细胞信号传导的负面调节影响，从而导致IL-2产生和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 下游途径的关键成分以及响应 CD28 共刺激调节肌动蛋白细胞骨架的成分。