IMMUNE POTENTIAL OF ANIMAL LACKING CLASS IA MOLECULES

描述(由申请人提供)：这项建议调查CD8T细胞在抵抗感染性病原体的免疫反应中的独特功能。我们主要关注CD8T细胞在感染单核细胞增多性李斯特菌(Lm)时先天免疫反应中所起的作用。我们最近证实，抗原非特异性CD8T记忆细胞通过分泌干扰素-γ参与细胞因子驱动的针对LM的先天反应。进一步将“天生”的CD8T细胞转移到干扰素-伽马缺乏的小鼠体内，可以保护它们免受LM的感染。我们认为CD8T细胞在干扰素-γ介导的先天免疫反应中起主要作用。在第一个目标中，我们研究了CD8和NK细胞在提供这种先天保护方面的相对效力。我们推测，已被证明在获得性免疫反应中起次要作用的效应CD8 T记忆细胞在先天免疫反应中起着重要作用，并将检验这一假说。在第二个目的中，我们将研究CD8中央记忆细胞(TMc)、透射电子显微镜和NK细胞在肝和脾中的定位。我们将使用CCR7结合趋化因子(CCL-19和-21)缺乏的小鼠来评估这种趋化因子-受体相互作用如何影响先天反应中的CD8 T细胞。我们还将利用新的表达Thy-1.1的BAC转基因小鼠作为干扰素-γ分泌的报告基因，以原位检测分泌干扰素-γ的CD8和NK细胞。在第三个目标中，我们将确定CD8T细胞在将初始的CD4T细胞极化为Th1亚群中的作用。在第四个目标中，我们将通过微阵列分析来检查由IL-12/18(天生)激活的CD8T细胞与通过TCR(适应性)激活的CD8T细胞的基因显示。综上所述，这项提议将为CD8T细胞如何在针对细胞内病原体的先天免疫反应中发挥作用增加重要的新信息。

DESCRIPTION (provided by applicant): This proposal investigates a unique function for CD8 T cells in the immune response against infectious agents. Our major focus is on the role that CD8 T cells play in the innate immune response during infection with Listeria monocytogenes (LM). We recently demonstrated that antigen non specific CD8 T memory cells participate in a cytokine driven innate response against LM by secreting interferon-gamma. Further transfer of "innate" CD8 T cells into interferon-gamma deficient mice protects them from infection with LM. We propose that CD8 T cells play a major role in the INF-gamma mediated innate response. In the first Aim we investigate the relative potency of CD8 vs NK cells in providing this type of innate protection. We postulate that effector CD8 T memory cells (TEM) which have been shown to play a minor role in the adaptive immune response play an important role in the innate response and will test this hypothesis. In the second Aim we will examine the localization of CD8 central memory cells (TCM), TEM, and NK cells at sites of LM infection in spleen and liver. We will use mice deficient in CCR7 binding chemokines (CCL-19 and -21) to assess how this chemokine-receptor interaction affects CD8 T cells in the innate response. We will also utilize new BAC transgenic mice that express Thy-1.1 as a reporter for IFN-gamma secretion to examine IFN-gamma secreting CD8 and NK cells in situ. In the third Aim we will determine the role of CD8 T cells in polarizing naive CD4 T cells to the Th1 subset. In the fourth Aim we will examine by microarray analysis the gene display of CD8 T cells that are activated by IL-12/18 (innate) vs those that are activated through the TcR (adaptive). In summary, this proposal will add important new information on how CD8 T cells function in the innate immune response against intracellular pathogens.