Vaccinia Inhibition of gd T cells is a Immune Evasion Mechanism

描述(由申请人提供)：Gammadelta T细胞使用MHC的替代受体，不受限制 在人体的所有淋巴组织中都能识别和识别。这个 Gammadelta(Gd)细胞识别病毒或细胞内细菌感染的细胞、肿瘤细胞和小细胞 分子抗原。一个主要的问题是：抗人类病毒需要gd T细胞吗？ 疾病？以前的研究，包括我们自己在艾滋病毒疾病方面的工作，为gdt提供了相关数据 细胞在病毒疾病中的作用，但在人类或非人类灵长类系统中还没有令人信服的研究 而且行动机制还没有定义。利用牛痘感染的模型，我们将 确定是否需要gdT细胞，并确定它们对保护性免疫的贡献。 牛痘是一种针对人类天花的天然减毒疫苗。GdT细胞对于 在小鼠的痘苗免疫中，它们在没有CD4+细胞和 随着中和抗体的发展，促进IgM向Ig G同型转换，尽管相似 在灵长类物种中，gT细胞的功能还没有研究过。我们自己的工作揭示了一种强有力的、 痘苗病毒对人GdT细胞的抑制作用。免疫逃避机制通常表明 靶细胞(这里是GdT细胞)是保护性反应的一部分。这项提案中的研究试图 确定牛痘病毒介导的抑制人GdT细胞的机制，以测试细胞因子和TLR 用于逆转抑制能力的激动剂，并在非人类灵长类动物中进行初步研究 检测gd T细胞在牛痘免疫发展中的作用。在这份提案中工作， 代表Pauza小组、圣路易斯大学Hoft实验室、Bernie Moss在 来自中国疾控中心的NIH/NIAID和邵一鸣，对推动我们的 了解gd T细胞，用于评估病毒疾病的新治疗方法，以改进 通过刺激gd T细胞的疫苗效力，以及努力产生更安全和更具免疫原性的疫苗 牛痘作为天花疫苗或病毒载体。人类主要的GdT细胞亚群可以在 体内与现有的临床药物，一个方向正在测试的新疗法的癌症和类似的 这些方法可能对病毒性疾病和疫苗接种有用。人类淋巴细胞的一个亚群称为 Gammadelta(Gd)T细胞被认为对病毒疾病的保护性免疫很重要 但现有的研究提供了与疾病的相关性，还没有证明这一要求或定义 对他们的贡献的行动机制。最近，我们发现牛痘病毒(天然的 正在出现的天花疫苗)可以有效地抑制gdT细胞，这表明它们是 控制人类牛痘感染的机制。我们的目标是测试gdT细胞 是病毒免疫所必需的，并追求新疗法的开发和改进 包括直接刺激gdT细胞的疫苗接种方法。

DESCRIPTION (provided by applicant): Gammadelta T cells use an alternative receptor for MHCunrestricted recognition and are found in all lymphoid compartments of the human body. The gammadelta (gd) cells recognize cells infected by virus or intracellular bacteria, tumor cells and small molecule antigens. A major question is: Are gd T cells are required for protection against human viral diseases? Previous studies including our own work on HIV disease, provided correlative data for a gd T cell role in viral disease but there are no compelling studies in human or nonhuman primate systems and mechanisms of action have not been defined. Using the model of vaccinia infection, we will determine whether gd T cells are required and define their contributions to protective immunity. Vaccinia is a naturally attenuated vaccine against smallpox in man. The gd T cells are essential for vaccinia immunity in the mouse, where they provide T cell help in the absence of CD4+ cells and promote IgM to IgG isotype switching with the development of neutralizing antibodies although similar functions for g T cells have not been studied in primate species. Our own work revealed a potent, vaccinia-mediated inhibition of human gd T cells. Immune evasion mechanisms generally indicate that the target cells (here gd T cells) are part of the protective response. Studies in this proposal seek to define the mechanism for vaccinia-mediated inhibition of human gd T cells, to test cytokines and TLR agonists for the ability to reverse inhibition, and to perform pilot studies in nonhuman primates for testing the role of gd T cells in the development of vaccinia immunity. Work in this proposal, representing efforts of the Pauza group, the Hoft laboratory in St. Louis University, Bernie Moss at the NIH/NIAID and Yiming Shao from the China CDC, are highly significant for advancing our understanding of gd T cells, for evaluating novel therapeutic approaches to viral disease, for improving vaccine efficacy by stimulating gd T cells, and for efforts to generate safer and more immunogenic vaccinia as smallpox vaccines or as viral vectors. The major human gd T cell subset can be activated in vivo with existing clinical drugs, a direction being tested in novel therapies for cancer, and similar approaches may be useful for viral diseases and vaccination. A subset of human lymphocytes called gammadelta (gd) T cells, are postulated to be important for protective immunity against viral diseases but existing studies provide correlations with disease and have not proven the requirement or defined a mechanism of action for their contribution. Recently, we showed that vaccinia virus (the naturally occurring vaccine against smallpox) potently inhibits gd T cells, suggesting they are part of the mechanism that controls vaccinia infection in man. Our goals are to test the hypothesis that gd T cells are necessary for viral immunity and to pursue the development of new therapies and improved vaccination approaches that incorporate direct stimulation of gd T cells.