Cytotoxic T Cell Responses to Virus Infection

细胞毒性 T 细胞对病毒感染的反应

基本信息

批准号：
8524204
负责人：
J. Lindsay Whitton
金额：
$ 47.38万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2014-08-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): CD8+ memory T cells are one of the cornerstones of successful vaccination, and much is known about their generation, i.e. the pathways that determine na¿ve CD8+ T cell activation, expansion & contraction, and the factors that affect the establishment of CD8+ memory T cell subsets. In contrast, we know relatively little about CD8+ memory T cell recall responses, upon which vaccine efficacy relies. Memory cells deal with individual virus-infected cells in vivo and, to do so effectively, they must respond to secondary infection (i.e., begin their recall response) by imposing their effector functions upon an infected cell before virus progeny has been released; for many virus infections, this means that - if they are to be maximally protective - memory T cells must act within hours of infection. Hence, my lab recently has begun to investigate the very early (d24 hours p.i.) recall responses of CD8+ memory T cells; and, so far as is possible, we measure the responses in vivo. Unpublished data (presented herein) show that: (i) CD8+ memory T cells initiate effector responses to virus infection in vivo within 3-6 hours (long before a single round of virus replication has been completed); and (ii) very surprisingly, in vivo cytokine synthesis (IFN¿, TNF & IL-2) is largely terminated soon thereafter (by 24 hours p.i.). This termination of effector function occurs despite the presence of immunostimulatory viral antigen, suggesting that there is active down-regulation of effector function by CD8+ memory T cells that have responded to infection. These events occur before the memory T cells have multiplied. These early recall responses, and the molecular mechanisms that control them, will be explored in four Specific Aims. 1. To investigate the in vivo regulation of CD8+ memory T cell early recall responses. Our observations regarding the rapid on/off expression of effector functions by CD8+ memory T cells will be expanded. 2. To identify and manipulate the molecular pathway(s) underpinning the early recall response of CD8+ memory T cells. The molecular mechanisms regulating the initiation, and the termination, of effector function(s) will be identified using several approaches. 3. To evaluate the role of dendritic cells in regulating these very early memory T cell responses. The majority of studies of DC / T cell interactions have (understandably) focused on priming of na¿ve T cells. Here, we shall evaluate the role of DCs in the rapid in vivo responses of CD8+ memory T cells. 4. To generate and test a mouse line that would allow us, for the first time, to evaluate the importance of various proteins in regulating the recall responses of CD8+ memory T cells. We shall generate a transgenic mouse line which will allow the investigator to deletion a gene from CD8+ T cells at the time of his/her choosing. An infected mouse would mount a completely normal primary T cell response, and would establish a normal memory cell pool; only then would we delete the gene of interest.

描述：CD8+记忆t -cells是成功疫苗的基石，即确定NA¿的途径VE CD8+ T细胞的激活，扩展和收缩，以及CD8+记忆T细胞子集的建立，对CD8+记忆T细胞回忆反应很少，他们必须应对继发感染（即开始召回反应）FFECTOR功能。病毒后代之前的细胞会在感染后数小时内具有最大保护性的作用。 T细胞在3-6个小时内启动对体内的效应子反应（在病毒复制之前很久）。在MELL乘以HAT的情况下，会在四个特定的AM中探索免疫刺激性病毒抗原AVE事件。 CD8+记忆T细胞的效应函数将扩展2。使用偏僻的方法。 VE T细胞首次评估各种蛋白质在调节CD8+记忆T细胞的召回响应中的重要性感染的小鼠将安装完全正常的Primaly T细胞反应，并建立正常的记忆细胞池。