T cell function in murine gammaherpesvirus infection

描述（由申请人提供）：人γ疱疹病毒、EB病毒和人疱疹病毒-8对免疫抑制个体如艾滋病患者造成严重的健康问题。抗病毒T细胞的免疫监视通常包含受感染的细胞，但是当这种免疫监视失败时，病毒转化的细胞可以生长并引起疾病。对γ疱疹病毒的CD 8 T细胞应答相对较好地表征，但人们越来越认识到CD 4 T细胞应答也可能在免疫监视中发挥重要作用。然而，在人类系统中不可能详细剖析γ疱疹病毒特异性CD 4 T细胞的功能和体内活性。因此，我们转向一个高度听话的小鼠模型，鼠γ疱疹病毒-68，以解决有关CD 4 T细胞反应的重要问题。阻碍CD 4 T细胞应答的详细研究的一个重要问题是它们以非常低的频率存在。在这里，我们通过使用一种系统来避免这个问题，在该系统中，使用T细胞受体转基因CD 4 T细胞和含有适当抗原的重组MHV-68，在感染前增加CD 4 T细胞的频率。然后，该系统可用于跟踪感染进展时的病毒特异性CD 4 T细胞应答。在具体目标1中，我们将使用该系统来确定MHV-68感染中CD 4 T细胞应答的功能和表型特征。此外，我们将确定维持CD 4 T细胞应答所需的因素，以便它能够长期耐受。在具体目标2中，我们将重点关注CD 4 T细胞应答的另一个重要作用-树突状细胞的许可。这种CD 40依赖性过程对于CD 4 T细胞对CD 8 T细胞应答的“帮助”的传递是必要的。在这个目标中，我们将确定在存在或不存在CD 40的情况下树突状细胞的生物学如何变化，以在分子水平上理解MHV-68感染期间的许可。我们的第三个具体目标集中在缺乏T细胞帮助的小鼠中MHV-68感染失控背后的机制。我们的初步数据详细说明了一种在CD 40缺陷小鼠中重新建立MHV-68感染控制的方法，其中病毒在肺部自发地重新激活。因此，本节建议了解这种效应背后的确切机制，这可能对患有复发性γ疱疹病毒感染引起的疾病的艾滋病患者具有重要的治疗益处。

DESCRIPTION (provided by applicant): The human gammaherpesviruses, Epstein-Barr virus and Human Herpesvirus-8, pose significant health problems in immunosuppressed individuals such as AIDS patients. Immune surveillance by antiviral T cells normally contains infected cells, however when this immune surveillance fails virus-transformed cells can outgrow and cause disease. The CD8 T cell response to gammaherpesviruses is relatively well characterized, but there is a growing appreciation that the CD4 T cell response may also play an important role in immune surveillance. However, a detailed dissection of the function and in vivo activity of gammaherpesvirus-specific CD4 T cells is not possible in human systems. Therefore we turned to a highly tractable mouse model, murine gammaherpesvirus-68, to address important questions regarding the CD4 T cell response. One significant problem which hinders the detailed study of CD4 T cell responses is that they are present at a very low frequency. Here we avoid this problem by using a system where the frequency of CD4 T cells is enlarged prior to infection, using T cell receptor transgenic CD4 T cells and recombinant MHV-68 containing the appropriate antigen. This system can then be used to track the virus-specific CD4 T cell response as the infection progresses. In Specific Aim 1 we will use this system to determine the functional and phenotypic characteristics of the CD4 T cell response in MHV-68 infection. In addition we will determine the factors necessary for sustaining the CD4 T cell response so that it can endure long-term. In Specific Aim 2 we will focus on another important role of the CD4 T cell response - licensing of dendritic cells. This CD40-dependent process is necessary for the transmission of CD4 T cell 'help' to the CD8 T cell response. In this aim we will determine how the biology of dendritic cells changes in the presence or absence of CD40, to understand licensing during MHV-68 infection on a molecular level. Our third Specific Aim focuses on the mechanism behind the loss of control of MHV-68 infection in mice deficient in T cell help. Our preliminary data detail a method of re-establishing control of MHV-68 infection in CD40-deficient mice, where the virus spontaneously reactivates in the lungs. Therefore this section proposes to understand the precise mechanism behind this effect, which may have important therapeutic benefit in AIDS patients suffering from disease caused by recurrent gammaherpesvirus infection.