Impact of Aging on CD4 Immunity to Flu

增龄对流感免疫功能的影响。 我们已经定义了免疫系统反应中广泛的年龄相关缺陷，特别是在幼稚的CD4T细胞中，这些细胞产生较差的效应反应和记忆受损细胞的产生。在第一个资金周期中，我们发现促炎细胞因子(IL-1、IL-6和TNFa)可以逆转效应器生成中的许多缺陷，而刺激免疫细胞的病毒产品的替代品称为TLR激动剂，通过DC向T细胞递呈抗原来诱导这些物质的产生。我们发现DC在同源相互作用过程中产生的IL-6是增加反应性老化的初始CD4T细胞的增殖和阻止其死亡的关键。这种激活也在一定程度上恢复了记忆反应。现在，我们将使用以下组合来定义导致NATve CD4T反应“拯救”的分子途径 体外还原方法和精心设计的采用转移模型，这将使我们能够确定所涉及的细胞和分子机制。我们将使用高度易处理的TCRTG模型以及多克隆研究来剖析机制。我们将分析体内的救援途径，并将研究扩展到小鼠的CDS T细胞以及人类的CD4和CDS T细胞(项目5的一部分)。这些研究 将产生重要的信息，这些信息可能有助于未来开发更好的策略，使用TLR激动剂，以更有效地为老年人接种疫苗，我们希望能够开发出关于T细胞如何衰老的统一理论，存在哪些缺陷，哪些缺陷可以克服，以及如何在小鼠和人身上进行。

Impact of Aging on CD4 Immunity to Flu. We have defined extensive age-associated defects in immune system response particulariy in naive CD4 T cells that give poor effector responses and the generation of impaired memory cells. In the first funding cycle we found that pro-inflammatory cytokines (IL-1, IL-6 and TNFa) could reverse many of the defects in effector generation, and that surrogates of viral products that stimulate immune cells, called TLR agonists, induce production of these by DC presenting antigen to the T cells. We identified IL-6 production by DC during the cognate interaction as key for increasing expansion and blocking death of responding aged naive CD4 T cells. The activation also restores memory responses to some extent. Now we will define the molecular pathways leading to the "rescue" of the naTve CD4 T responses using a combination of reductionist in vitro approaches and carefully designed adoptive transfer models, that will allow us to determine the cellular and molecular mechanisms involved. We will use highly tractable TcR Tg models as well as polyclonal studies to dissect mechanisms. We will analyze rescue pathways in vivo as well as extend the studies to CDS T cells in mouse and to human CD4 and CDS T cells (part of Project 5). These studies will generate important information that could contribute to the development in future of better strategies, using TLR agonists, to more effectively vaccinate the elderiy and we expect to be able to develop a unified theory of how aging develops in T cells, what defects exist and which can be overcome and how in mice and man.