Immune surveillance in murine gammaherpesvirus infection

描述（由申请人提供）：人类伽玛疱疹病毒与重大疾病相关，在艾滋病患者中尤为普遍。在这些患者中，病毒转化的细胞可以不受控制地生长成肿瘤，如非霍奇金淋巴瘤、原发性中枢神经系统淋巴瘤和卡波西肉瘤。这些疾病的发生是由于病毒潜伏感染的结果，因此了解潜伏期间的免疫控制是至关重要的。我们建议使用小鼠γ疱疹病毒模型来研究免疫监视机制的几个方面。具体来说，我们将测试以下假设：(i)裂解性和潜伏性抗原特异性CD8 T细胞对γ疱疹病毒潜伏期的控制有不同的贡献。我们将用T细胞系重组潜伏感染的免疫缺陷小鼠，这些T细胞系对潜伏或裂解病毒抗原具有特异性，并确定哪一种能够维持对病毒的控制。我们还将确定这些细胞控制病毒的机制。（ii）不同的效应/记忆T细胞群在控制潜伏感染中发挥不同的作用。效应/记忆T细胞在表面标记物、效应功能和迁移方面具有异质性。CD62L是部分定义这些群体的一个标记。我们将使用过继转移系统检查CD62Lhi和CD62LIo细胞在潜伏感染期间的作用。（iii）参与免疫监视的病毒特异性CD8 T细胞以不同于传统记忆性CD8 T细胞的方式受到调节。我们的初步数据表明，与传统的记忆T细胞不同，mhv -68特异性CD8 T细胞不需要IL-15来进行增殖更新。因此，我们将确定在潜伏感染期间是什么调节这些CD8 T细胞，特别关注所涉及的细胞因子和调节性CD4+CD25+ T细胞的作用。本提案中描述的工作将为尚不清楚的伽玛疱疹病毒感染免疫监测过程提供重要信息。此外，其中一些信息也可能导致对其他慢性病毒感染或肿瘤细胞的免疫监视有更深入的了解。这项工作将导致更好的治疗方法来对抗肿瘤相关的病毒感染。

DESCRIPTION (provided by applicant): Human gammaherpesviruses are associated with significant disease, and these are particularly prevalent in AIDS patients. In these patients virus-transformed cells can grow uncontrolled into tumors such as non-Hodgkin's lymphoma, primary CNS lymphoma and Kaposi's sarcoma. Such diseases occur as a consequence of latent infection by the virus, and it is therefore critical to understand the immunological control during latency. We propose to investigate several aspects of the immune surveillance mechanism using a mouse gammaherpesvirus model. Specifically we will test the following hypotheses: (i) That lytic and latent antigen-specific CD8 T cells make different contributions to the control of gammaherpesvirus latency. We will reconstitute latently-infected immunodeficient mice with T cell lines specific for either latent or lytic virus antigens and determine which ones are able to maintain control of the virus. We will also determine the mechanism by which these cells to control the virus. (ii) That different effector/memory T cell population play different roles in the control of latent infection. Effector/memory T cells have been found to be heterogeneous with respect to surface markers, effector function and migration. One marker that partly defines these populations in is CD62L. We will examine the roles of CD62Lhi and CD62LIo cells during latent infection using an adoptive transfer system. (iii) That virus-specific CD8 T cells involved in immune surveillance are regulated in a different manner to conventional memory CD8 T cells. Our preliminary data indicates that, unlike conventional memory T cells, MHV-68-specific CD8 T cells do not require IL-15 for proliferative renewal. We will therefore determine what regulates these CD8 T cells during the latent infection, with specific focus on the cytokines involved and the role of regulatory CD4+CD25+ T cells. The work described in this proposal will provide essential information to the poorly understood process of immune surveillance in gammaherpesvirus infections. In addition some of this information may also lead to a greater understanding of immune surveillance to other chronic virus infections or tumor cells. This work will lead to better therapies to combat tumor-associated virus infections.