Receptor Organization, SMAC Dynamics and membrane Lipids in Aging T Cells

衰老 T 细胞中的受体组织、SMAC 动力学和膜脂质

• 批准号: 7334511
• 负责人: Abraham Kupfer
• 金额: $ 26.75万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7334511
• 关键词: Affect; Age; Aging; American; Animals; Antibodies; Antigen-Presenting Cells; Antigens; Artificial nanoparticles; Binding; Biophysics; Blinking; CD4 Positive T Lymphocytes; Cell Aging; Cell Nucleus; Cell membrane; Cell physiology; Cells; Cellular Immunity; Chimera organism; Cholesterol; Chromosome Pairing; Communicable Diseases; Complex; Cytoskeleton; DNA Sequence Rearrangement; Defect; Diet; Disruption; Dissociation; Economics; Event; Fluorescent Antibody Technique; Genetic Transcription; Green Fluorescent Proteins; Image; Immune; Immune response; Immunity; Impairment; Individual; Infection; Intervention; Intracellular Signaling Proteins; Invaded; Kinetics; Label; Lateral; Lead; Life; Lipids; Localized; Membrane; Membrane Lipids; Microscopy; Modification; Molecular; Monoclonal Antibody HuM291; Muromonab-CD3; Mus; Not Defined; Older Population; Optics; Pattern; Peptide/MHC Complex; Peptides; Phenotype; Phospholipids; Polyunsaturated Fatty Acids; Process; Proteins; Quantum Dots; Receptor Signaling; Recombinants; Recruitment Activity; Reporting; Resistance; Resolution; Secondary to; Signal Transduction; Signaling Molecule; Stimulus; Surface Antigens; Synapses; T memory cell; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Time; Total Internal Reflection Fluorescent; Transgenic Mice; Vaccines; age effect; age related; aged; base; cell age; cellular imaging; digital; experience; immunological synapse; loss of function; nanoscale; oxidation; pathogen; receptor; receptor function; research study; response; social; synaptogenesis

DESCRIPTION (provided by applicant): Aging is associated with reduced protective cellular as well as systemic immune responses. Protective cellular immunity against invading pathogens depends on the ability of T cells to detect processed pathogen-derived peptides that are bound to MHC proteins on the surface of antigen- presenting cells (APCs). In young people and mice binding of the T cell receptor (TCR), on the membrane of the T cells, to such peptides-MHC proteins on the APCs causes localized spatial- temporal membrane rearrangements that recruit and activate receptor-proximal intracellular signaling proteins. The engaged receptors and their associated intracellular proteins rapidly form highly organized Immunological-Synapses (IS). These membrane-proximal events within the IS initiate multiple intracellular signaling cascades that propagate from the membrane to the nucleus, modify gene transcription and cause effective T cell immune responses. In aging people and mice both na¿ve and memory T cells respond poorly to antigenic stimulation by APCs and form defective immune synapses. The causes for these age-dependent defects are still unknown. In this project we will study membrane-associated events in T cells from aging mice. We propose to investigate the connection between declines in immune response with aging to changes in TCR organization, IS dynamics and membrane lipid composition. Our hypothesis is that declines in CD4+ T cell responses reflect changes in TCR organization, which reduce effective antigen recognition. We further speculate that the changes in receptor organization are a consequence of changes plasma membrane lipid composition with age. We will test our hypothesis by: 1) using engineered nano-particles, quantum-dots, to probe and analyze TCR organization in the plasma membrane of T cells from young and old animals 2) 4D live cell imaging of immune synapse formation to capture subtle kinetic changes in antigen recognition consequent to aging and 3) determining the lipid composition of T cells from young and aged mice and using this as a guide to lipid modulation of TCR organization and dynamics of IS formation. The experiments proposed can lead to a better understanding of age-dependent changes in immune responses at the cellular and molecular level. They can also point the way to relatively simple interventions, for example dietary changes, which can enhance immune responses in older individuals. Immune responses decline with age resulting in decreased resistance to infectious diseases and reduced protection by vaccines. In this application we intend to investigate the causes for age- dependent reduced immunity. Our experiments can point the way to simple approaches, changes in diet, for modulating and enhancing immune responses in aged individuals. If these declines could be arrested or reduced the large population of older Americans would be less susceptible to infection with profound social and economic consequences.

描述（由申请人提供）：衰老与保护性细胞以及全身免疫应答降低有关。针对入侵病原体的保护性细胞免疫取决于T细胞检测与抗原呈递细胞（APC）表面上的MHC蛋白结合的加工的病原体衍生肽的能力。在年轻人和小鼠中，T细胞膜上的T细胞受体（TCR）与APC上的此类肽-MHC蛋白的结合引起局部时空膜重排，其募集并激活受体近端细胞内信号传导蛋白。参与的受体及其相关的细胞内蛋白迅速形成高度组织化的免疫突触（IS）。IS内的这些膜近端事件启动从膜传播到细胞核的多个细胞内信号传导级联，修饰基因转录并引起有效的T细胞免疫应答。在老年人和小鼠中，幼稚和记忆T细胞对APC的抗原刺激反应较差，并形成有缺陷的免疫突触。这些年龄依赖性缺陷的原因仍然未知。在这个项目中，我们将研究衰老小鼠T细胞中的膜相关事件。我们建议调查免疫应答下降与TCR组织，IS动力学和膜脂质组成的变化之间的联系。我们的假设是，CD 4 + T细胞应答的下降反映了TCR组织的变化，这降低了有效的抗原识别。我们进一步推测，受体组织的变化是随着年龄的变化质膜脂质组成的结果。我们将通过以下方式检验我们的假设：1）使用工程纳米粒子，量子点，2）免疫突触形成的4D活细胞成像，以捕获衰老后抗原识别的微妙动力学变化，以及3）确定来自年轻和老年小鼠的T细胞的脂质组成，并将其用作TCR组织的脂质调节和IS形成的动力学的指导。所提出的实验可以导致在细胞和分子水平上更好地理解免疫应答的年龄依赖性变化。它们还可以为相对简单的干预措施指明方向，例如改变饮食，这可以增强老年人的免疫反应。免疫反应随着年龄的增长而下降，导致对传染病的抵抗力下降，疫苗的保护作用也降低。在本申请中，我们打算调查年龄依赖性免疫力降低的原因。我们的实验可以指出简单的方法，改变饮食，调节和增强老年人的免疫反应。如果这些下降可以被阻止或减少，那么大量的美国老年人就不那么容易受到感染，从而产生深远的社会和经济后果。