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：
9027294
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
项目类别：
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/9027294
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 CD80 gene CD8B1 gene Cell Communication Cell surface Cells Chemicals Collaborations Cytoplasmic Tail Cytoskeleton Data Dendritic Cells Development Elements Ensure Experimental Models Genetic Hydrolysis Immune response Immune system Infection Interleukin-2 Lead Ligands Malignant Neoplasms Mature T-Lymphocyte Mediating 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 public health relevance response rho GTP-Binding Proteins small molecule inhibitor src-Family Kinases thymocyte

项目摘要

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（由适用提供）：CD28是T细胞表面分子，与固定的TCR配体结合使用时，可以提供第二个信号，以诱导幼稚的t激活。 CD28与其配体CD80（B7.1）和CD86（B7.2）的相互作用引起的共刺激是通过激活先天免疫系统激活而引起的。我们对CD28如何介导其共刺激信号没有很好的分子理解。模型和实验证据表明，CD28要么：1）增加TCR信号的大小；或，2）提供了一个独特的信号，与TCR提供的质量不同。重要的是要了解共刺激的分子信号通路，因为在临床上中断非常重要。更深入地了解 CD28信号通路可以使新疗法的发展有助于阻断免疫系统。我实验室的最新研究提供了一些新的见解，并提出了方法和线索，这些方法和线索将使我们以前未被认可的CD28调节信号通路的组成部分，并允许对CD28信号传导有更全面的了解。这些化学生物学，遗传学和蛋白质组学研究使我们假设CD28共刺激的重要结果是调节肌动蛋白细胞骨架，这影响了TCR下游的信号。我们将通过以下特定目的探讨这一点：1）确定cost刺激调节肌动蛋白细胞骨架的机制，以促进PLCγ1在双阳性（CD4+CD8+，DP）胸腺细胞和更成熟的T细胞中介导的PIP2介导的PIP2水解； 2）确定CD28如何克服PYK2和CBL-B对T细胞信号传导的负调控作用，从而导致IL-2产生和T细胞增殖； 3）使用最近获得的磷酸蛋白质组学数据，我们将确定CD28下游途径的关键组成部分，以及那些根据CD28 castimulation调节肌动蛋白细胞骨架的关键组成部分。