Immune surveillance in murine gammaherpesvirus infection

描述(申请人提供)：人类伽马疱疹病毒与重大疾病有关，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、原发中枢神经系统淋巴瘤和卡波西肉瘤。这种疾病的发生是由于病毒的潜伏感染，因此了解潜伏期间的免疫控制是至关重要的。我们建议使用小鼠伽马疱疹病毒模型来研究免疫监视机制的几个方面。具体地说，我们将检验以下假设：(I)裂解和潜伏抗原特异性CD8T细胞在控制伽马疱疹病毒潜伏期方面做出了不同的贡献。我们将用针对潜伏或裂解病毒抗原的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。(2)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。已发现效应器/记忆性T细胞在表面标志、效应器功能和迁移方面是不同的。部分定义这些人群的一个标记是CD62L。我们将使用过继转移系统检测CD62Lhi和CD62LIo细胞在潜伏感染过程中的作用。(Iii)参与免疫监视的病毒特异性CD8 T细胞的调节方式不同于传统的记忆性CD8 T细胞。我们的初步数据表明，与传统的记忆性T细胞不同，MHV-68特异性CD8T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，特别是涉及的细胞因子和调节CD4+CD25+T细胞的作用。这项提案中描述的工作将为对伽马疱疹病毒感染进行免疫监测这一鲜为人知的过程提供必要的信息。此外，这些信息中的一些还可能有助于更好地理解对其他慢性病毒感染或肿瘤细胞的免疫监视。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.