Regulation of CD28 Signaling in T cells by Cytoplasmic Domain Membrane Binding

通过细胞质域膜结合调节 T 细胞中的 CD28 信号转导

基本信息

批准号：
8307875
负责人：
Jessica Kohler
金额：
$ 3.36万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8307875
关键词：
Address Affinity Animal Model Antigen-Presenting Cells Antigens Autoantigens Autoimmune Diseases Autoimmunity Binding Biochemical Biological Assay Biological Models CD28 Antigens CD28 gene CD80 gene Cell Survival Cell membrane Cell physiology Cell-Free System Cells Cellular Assay Charge Cytoplasmic Tail DNA Sequence Rearrangement Data Defect Dose Effector Cell Event Experimental Autoimmune Encephalomyelitis Fluorescence Resonance Energy Transfer Gene Transfer Genomics Goals ITAM Immune Immune system Immunologic Receptors Individual Infection Insulin-Dependent Diabetes Mellitus Isoelectric Point Lead Ligand Binding Ligands Lipid Binding Lipids Measures Mechanics Membrane Microscopy Modeling Multiple Sclerosis Mus Peptides Phosphotransferases Phosphotyrosine Physiological Process Production Receptor Signaling Regulation Research Research Project Grants Rheumatoid Arthritis Signal Transduction Signaling Protein Stem cells Surface System T memory cell T-Cell Activation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Tyrosine Tyrosine Phosphorylation V(D)J Recombination Work base cellular imaging cytokine human CD3E protein improved in vitro Assay in vivo Model insight intercellular communication mutant pathogen prevent receptor reconstitution response retroviral-mediated

项目摘要

The T cell receptor (TCR) is generated by rearrangement of V, D and J segments in individual cells at the genomic level. Therefore, the TCR repertoire collectively can recognize any antigen. As a consequence of this random rearrangement process, T cells lack the ability to discriminate between self antigens and pathogen- associated antigens. Instead, T cells must be activated by innate immune antigen presenting cells (APCs) and instructed to differentiate into effector cells. This activating signal requires antigen-dependent stimulation of the TCR and costimulation through CD28, which is a membrane receptor constitutively expressed on all naove T cells and subsets of memory T cells. Binding to its ligands B7.1 (CD80) or B7.2 (CD86) expressed on APCs activated by recognition of pathogen-associated molecules delivers a costimulatory signal that synergizes with TCR signaling and promotes cell survival, proliferation and effector functions. The mechanism by which ligand engagement by TCR or CD28 leads to receptor triggering and signal transduction remains unknown; a general mechanism of receptor triggering remains to be elucidated for any phosphotyrosine-based immune receptor. Conversely, the mechanism preventing spontaneous and aberrant signaling of CD28 and other phosphotyrosine-based receptors is also poorly understood. Using a combination of fluorescence resonance energy transfer (FRET) microscopy, biochemical and cellular assays to assess T cell signaling and function, and an in vivo model of multiple sclerosis (murine experimental autoimmune encephalomyelitis), this research will examine: a) association of CD28 cytoplasmic domain (CD28CD) with the inner leaflet of the plasma membrane; b) the consequences of this association for regulation of signaling and T cell function; and c) the mechanism by which CD28CD is released from the plasma membrane under physiological conditions. Mechanistic understanding of CD28 regulation would provide insight into a more generalizable model of receptor triggering.

T细胞受体（TCR）是通过基因组水平的单个细胞中V，D和J段重排的。因此，TCR曲目集体可以识别任何抗原。由于这种随机重排过程，T细胞缺乏区分自抗原和病原体抗原的能力。取而代之的是，必须通过先天免疫抗原呈递细胞（APC）激活T细胞，并指示分化为效应细胞。该激活信号需要通过CD28对TCR的抗原依赖性刺激，这是一种膜受体，该膜受体在所有NAOVE T细胞和记忆T细胞的子集上组成型表达。通过识别与病原体相关的分子识别的APC表达的APC的配体B7.1（CD80）或B7.2（CD86）的结合，传达了一个cotimutimutation Signals信号，与TCR信号传导协同并促进细胞存活，增殖，增殖，效应子功能。 TCR或CD28导致受体触发和信号转导的配体参与的机制尚不清楚。对于任何基于磷酸酪氨酸的免疫受体，仍尚待阐明受体触发的一般机制。相反，也很少了解到CD28和其他基于磷酸酪氨酸的受体的自发和异常信号传导的机制。结合荧光共振能量转移（FRET）显微镜，生化和细胞测定法来评估T细胞信号传导和功能，以及多发性硬化症的体内模型（Murine实验性自身免疫性脑脊髓炎），该研究将检查： b）这种调节信号传导和T细胞功能的关联的后果； c）在生理条件下从质膜中释放CD28CD的机制。对CD28调节的机械理解将提供对更概括的受体触发模型的见解。