T LYMPHOCYTE/LAMININ INTERACTIONS IN AGING

老年人的免疫功能下降导致更大的 易患疾病的，尤指由病毒引起的。最新研究 提出这样一种假设，即这种下降与能力的改变有关 白细胞从血液中迁移，通过基底 膜，并进入组织到感染部位。因为T 淋巴细胞(T-Ly)是对抗病毒的主要白细胞 感染和因为T-Ly通过三维迁移 胶原凝胶(细胞通过基底膜迁移的模型 进入组织)需要存在于细胞外基质的凝胶中 蛋白质层粘连蛋白，拟议的研究重点是与衰老相关的 T-Ly与层粘连蛋白相互作用的变化。的确， 已经进行的实验有力地支持了这一假设：T-Ly 从年长的个人迁移到 胶原蛋白/层粘连蛋白凝胶比年轻个体的T-Ly更容易。此外， 阿尔茨海默病可能是T细胞改变的一个极端例子 阿尔茨海默病T-Ly迁移过程中淋巴细胞-层粘连蛋白相互作用 不如对照高年级的T-Ly。为了进一步检验这一假设，我们 将：1)用流式细胞术比较不同细胞因子的表达 不同级别的T-Ly在老年人和年轻人中的分布。这些 实验将表明，老年人和老年人之间的功能差异 年轻的T-Ly是特定亚群扩增的结果 T-Ly在老年人中的应用。2)使用生化方法比较 层粘连蛋白受体在老年和青年T-Ly中的表达。我们有 已经证明了α-6和α-7整合素亚单位是 T-Ly中的功能层粘连蛋白受体。这些实验将表明 哪些层粘连蛋白受体负责差异相互作用 年长的和年轻的T-Ly和层粘连蛋白。3)因为蛋白激酶C (PKC)在调节T-Ly迁移方面发挥重要作用，我们将 比较PKC异构体的表达和亚细胞定位 在迁徙中老年和青年T-Ly的作用及相互作用 层粘连蛋白与特异性受体调节表达和 蛋白激酶C亚型的定位。这些实验将揭示如果 老年和青年T-Ly的功能差异是由于 层粘连蛋白受体与信号机制的联系差异 涉及PKC。更好地理解细胞迁移的作用 与衰老相关的免疫缺陷将由这些 研究应该允许新的战略来抗击传染病 老年人将被提出并接受测试。

Immune function declines in the elderly resulting in a greater susceptibility to disease, particularly of viral origin. Recent studies suggest the hypothesis that this decline involves alterations in the abilit of leukocytes to migrate from the bloodstream, through basement membranes, and into tissues to sites of infection. Because T lymphocytes (T-Ly) are the primary leukocytes that fight viral infections and because T-Ly migration through three-dimensional collagen gels (a model for cell migration through basement membranes into tissues) requires the presence in the gels of the extracellular matrix protein laminin, the proposed studies focus on aging-associated alterations in the interactions of T-Ly with laminin. Indeed, experiments already performed strongly support the hypothesis: T-Ly from senior individuals migrate much less well through collagen/laminin gels than do T-Ly from young individuals. Moreover, Alzheimer's Disease may be an extreme example of altered T lymphocyte-laminin interactions in that Alzheimer's T-Ly migrate even less well than control senior T-Ly. To test the hypothesis further, we will: 1) Use flow cytometry to compare the expression of markers for various classes of T-Ly in senior and young individuals. These experiments will indicate if functional differences between senior and young T-Ly result from the amplification of a specific subpopulation of T-Ly in seniors. 2) Use biochemical methods to compare the expression of laminin receptors by senior and young T-Ly. We have already demonstrated that the alpha-6 and alpha-7 integrin subunits are functional laminin receptors in T-Ly. These experiments will suggest which laminin receptors are responsible for the differential interaction of senior and young T-Ly with laminin. 3) Because protein kinase C (PKC) plays a major role in regulating T-Ly migration, we will compare the expression and subcellular localization of PKC isoforms in migrating senior and young T-Ly and the role of the interaction of laminin with specific receptors in regulating the expression and localization of PKC isoforms. These experiments will reveal if functional differences between senior and young T-Ly result from differences in the linkage of laminin receptors to signaling mechanisms involving PKC. The better understanding of the role of cell migration in immune deficits associated with aging that will result from these studies should allow new strategies for fighting infectious diseases in the elderly to be proposed and tested.