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

描述(由申请人提供)：衰老与保护性细胞和全身免疫反应降低有关。对入侵病原体的细胞免疫保护依赖于T细胞检测加工后的病原体衍生多肽的能力，这些多肽与抗原提呈细胞(APC)表面的MHC蛋白结合。在年轻人和小鼠中，T细胞膜上的T细胞受体(TCR)与APC上的这些肽-MHC蛋白结合导致局部的时空膜重排，招募并激活受体近端的细胞内信号蛋白。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了从膜到核的多个细胞内信号级联反应，修改基因转录，引起有效的T细胞免疫反应。在老年人和小鼠中，NA和记忆性T细胞对APC的抗原刺激反应很差，形成有缺陷的免疫突触。这些与年龄相关的缺陷的原因尚不清楚。在这个项目中，我们将研究衰老小鼠T细胞膜相关事件。我们建议研究随着年龄增长的免疫反应下降与TCR组织、IS动力学和膜脂组成变化之间的关系。我们的假设是，CD4+T细胞反应的下降反映了TCR组织的变化，这降低了有效的抗原识别。我们进一步推测，受体结构的变化是随着年龄的增长质膜脂组成发生变化的结果。我们将通过以下方式验证我们的假设：1)使用工程纳米粒子，量子点，来探测和分析年轻和老年动物T细胞质膜上的TCR组织；2)免疫突触形成的4D活细胞成像，以捕捉由于衰老而导致的抗原识别的细微动力学变化；3)测定年轻和老年小鼠T细胞的脂组成，并以此作为TCR组织的脂质调节和IS形成的动力学的指导。建议的实验可以在细胞和分子水平上更好地理解免疫反应随年龄的变化。他们还可以指出相对简单的干预措施，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，疫苗的保护作用减弱。在这项申请中，我们打算调查年龄相关性免疫力下降的原因。我们的实验可以为调节和增强老年人的免疫反应提供简单的方法，改变饮食。如果这些下降能够得到遏制或减少，美国大量老年人口就不那么容易受到感染，从而产生深远的社会和经济后果。

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.