Immune surveillance in murine gammaherpesvirus infection

描述（由申请方提供）：人γ疱疹病毒与重大疾病相关，在艾滋病患者中尤其普遍。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CNS淋巴瘤和卡波西肉瘤。这些疾病的发生是病毒潜伏感染的结果，因此了解潜伏期期间的免疫控制至关重要。我们建议使用小鼠γ疱疹病毒模型研究免疫监视机制的几个方面。具体而言，我们将测试以下假设：（i）裂解性和潜伏性抗原特异性CD 8 T细胞对γ疱疹病毒潜伏期的控制做出不同的贡献。我们将用对潜伏性或裂解性病毒抗原特异的T细胞系重建潜伏感染的免疫缺陷小鼠，并确定哪些细胞系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。已经发现效应/记忆T细胞在表面标志物、效应功能和迁移方面是异质的。部分定义这些群体的一个标志物是CD 62 L。我们将使用过继性转移系统检查CD 62 Lhi和CD 62 Lio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CD 8 T细胞的调节方式与传统的记忆性CD 8 T细胞不同。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CD 8 T细胞不需要IL-15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CD 8 T细胞，特别关注所涉及的细胞因子和调节性CD 4 + CD 25 + T细胞的作用。本提案中描述的工作将为γ疱疹病毒感染中免疫监测的知之甚少的过程提供重要信息。此外，这些信息中的一些也可能导致对其他慢性病毒感染或肿瘤细胞的免疫监视的更好理解。这项工作将导致更好的治疗方法来对抗肿瘤相关病毒感染。

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.