Vaccinia Inhibition of gd T cells is a Immune Evasion Mechanism

描述（由申请人提供）：γ δ T细胞使用MHC的替代受体，不受限制 识别，并发现在人体的所有淋巴隔室。的 γ δ（GD）细胞识别被病毒或细胞内细菌感染的细胞、肿瘤细胞和小 分子抗原。一个主要的问题是：gd T细胞是保护人类免受病毒感染所必需的吗？ 疾病？以前的研究，包括我们自己对HIV疾病的研究，为gd T提供了相关数据。 细胞在病毒性疾病中的作用，但在人类或非人类灵长类动物系统中没有令人信服的研究 作用机制尚未确定。使用牛痘感染模型，我们将 确定是否需要gd T细胞，并确定其对保护性免疫的贡献。 牛痘是一种天然减毒的人类天花疫苗。 在小鼠中的牛痘免疫，其中它们在缺乏CD 4+细胞的情况下提供T细胞帮助， 促进IgM向IgG同种型转换，并产生中和抗体，尽管与 尚未在灵长类物种中研究gT细胞的功能。我们自己的工作揭示了一种强大的， 牛痘介导的对人gd T细胞的抑制。免疫逃避机制通常表明， 靶细胞（此处为gd T细胞）是保护性应答的一部分。本建议中的研究旨在 明确牛痘介导的人gd T细胞抑制机制，检测细胞因子和TLR 激动剂的能力，逆转抑制，并进行试点研究，在非人灵长类动物， 测试gd T细胞在牛痘免疫发展中的作用。在这个提案中， 代表Pauza小组的努力，圣路易斯大学的Hoft实验室， NIH/NIAID和中国疾控中心的Yiming Shao，对于推进我们的研究具有重要意义。 对gd T细胞的了解，用于评估病毒性疾病的新治疗方法，用于改善 通过刺激gd T细胞来提高疫苗效力，并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作为病毒载体。主要的人gd T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 这些方法可用于病毒性疾病和疫苗接种。人类淋巴细胞的一个亚群， γ δ（gd）T细胞被认为对于抵抗病毒性疾病的保护性免疫是重要的 但是现有的研究提供了与疾病的相关性，并且还没有证明这种要求或定义一种 其贡献的作用机制。最近，我们发现，牛痘病毒（自然 天花疫苗）有效地抑制gd T细胞，表明它们是天花疫苗的一部分。 我们的目标是检验gd T细胞在人类中控制牛痘病毒感染的机制。 对于病毒免疫和追求新疗法的开发和改进是必要的 结合直接刺激gd T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.