Impact of Aging on CD4 Immunity to Flu

衰老对CD 4免疫力的影响 我们已经定义了免疫系统应答中广泛的年龄相关缺陷，特别是在初始CD 4 T细胞中，其产生不良的效应子应答和受损的记忆细胞的产生。在第一个资助周期中，我们发现促炎细胞因子（IL-1，IL-6和TNF α）可以逆转效应子产生中的许多缺陷，并且刺激免疫细胞的病毒产物的替代物（称为TLR激动剂）通过DC将抗原呈递给T细胞诱导这些产物的产生。我们鉴定了在同源相互作用期间DC产生的IL-6是增加应答的老化幼稚CD 4 T细胞的扩增和阻断其死亡的关键。激活也在一定程度上恢复记忆反应。现在，我们将使用以下组合来定义导致天然CD 4 T应答“拯救”的分子途径： 简化的体外方法和精心设计的过继转移模型，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TcR Tg模型以及多克隆研究来剖析机制。我们将分析体内的拯救途径，并将研究扩展到小鼠中的CDS T细胞以及人CD 4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在未来开发更好的策略，使用TLR激动剂，更有效地为老年人接种疫苗，我们希望能够开发一个统一的理论，关于T细胞如何衰老，存在什么缺陷，可以克服什么，以及如何在小鼠和人类中发展。

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.