Immunological control of a persistent viral infection

摘要 在缺乏有效的CD 4 T细胞功能的免疫受损接受者中，不能控制潜伏疱疹病毒尤其成问题。例如艾滋病患者或缺乏有效CD 4 T细胞功能的移植受者。鼠γ疱疹病毒-68（IVIHV-68）是一种啮齿类动物自然发生的病原体，它与鼠γ疱疹病毒-68（MHV-68）密切相关，后者与人类病原体Epstein巴尔病毒和卡波西肉瘤相关疱疹病毒密切相关。MHV-68感染小鼠为疱疹病毒的研究提供了一种易处理的小动物模型。用MHV-68感染小鼠为研究γ疱疹病毒感染的免疫控制、检测潜在感染能力和检测潜在再激活个体的能力提供了易处理的小动物模型。控制免疫受损个体中病毒再活化的治疗剂。CD 4 T细胞不是急性控制复制MHV-68所必需的，但却是长期有效控制所必需的，这突出了CD 40-CD 40 L相互作用在004 T细胞帮助控制中的重要性。我们的早期工作强调了CD 4 O-CD 4 OL相互作用在CD 4 T细胞中的重要性，有助于长期控制MHV-68，并表明单独使用CD 40激动剂，单独使用抗体，病毒再活化抗体，CD 4 O刺激足以防止CD 4 T细胞缺陷小鼠肺中的病毒再活化。细胞小鼠。CD 40刺激上调树突状细胞上的CD 80和86，其与CD 40刺激相互作用上调树突状细胞上的CD 80和86，其分别与阳性和阴性共刺激分子CD 28和CTLA-4相互作用。有趣的是，我们已经表明，已知的CD 80和86对于MHV-68的长期控制是必需的，尽管CD 80和86对于MHV-68的长期控制是必需的，但CD 28，唯一已知的CD 80/86的阳性共刺激受体不是必需的，这表明了新的所需的可能性，阳性共刺激受体为0 D80/86超家族，该受体。CD 28、CD 80和CD 86是CD 28-B7超家族的一部分，该超家族包括几种受体。0028，介导T细胞的阳性或阴性共刺激的CD 80成员。在本申请中，我们将介导T细胞的正或负共刺激的成员。在本申请中，我们将研究CD 40和CD 28-B7家族成员相互作用以调节细胞应答的机制，CD 8 T细胞应答在对γ疱疹病毒感染的应答期间。在目标I中，我们将感染。在目的1中，我们将研究为什么长期控制MHV-68需要CD 4 T细胞，但长期控制MHV-68不需要CD 4 T细胞，但不研究为什么004 T细胞（急性）控制对短期（急性）控制病毒至关重要。我们的数据显示两种病毒。CD 8 T细胞活化功能的替代途径在急性期间起作用，但在长期对照期间不起作用。在目的2中，我们将研究一种新的CD 80/86（B7-1，2）受体控制的可能性。在目的2中，我们将研究一种新型的0 D80/86（B7- 1）受体在MHV-68的长期控制中发挥作用的可能性。在目标3中，我们将研究PD-1在控制MHV-68中的作用。在目的3中，将在MHV-68的急性和长期控制中发挥作用，PD-1是一种抑制性B7家族成员，我们已经证明，在不存在抑制性B7家族成员的情况下，PD-1在008细胞上上调，我们已经证明，在不存在CD 4 T细胞的情况下，PD-1在CD 8 T细胞上上调。这些研究将提供重要的0 D4 T细胞，用于MHV-68的急性和长期控制。这些研究将提供对CD 8 T细胞介导急性和长期持续性病毒感染的急性和对照控制的机制差异的重要见解，并且在设计病毒和设计免疫抑制剂或疫苗以对抗复发性γ疱疹病毒感染中可能具有重要价值Sarawar，Sally 1 c>。 公司简介 3，p C '（0 fl？ 可以 0）3 CL） CSC BCD ：cum Ono 哦，-。哦 vo（Q 迟 �0= E 我...我... 0-0 第二章） 60, （00） ， �C�� p-0 ”“吃了。

ABSTRACT is particularly problematic in immunocompromised Failure to control latent herpesviruses is particularly problematic in immunocompromised recipients who lack effective CD4 T cell function. individuals such as AIDS patients or transplant recipients who lack effective CD4 T cell function. Murine gammaherpesvirus-68 (IVIHV-68) is naturally occurring rodent pathogen, which is closely Murine gammaherpesvirus-68 (MHV-68) naturally occurring rodent which is closely related to the human pathogens Epstein Barr virus and Kaposi's sarcoma-associated related to the human pathogens Epstein virus and Kaposi's sarcoma-associated herpesvirus. Infection of mice with MHV-68 provides a tractable small animal model for studying herpesvirus. Infection mice with MHV-68 provides tractable small animal model for studying immunological control of gammaherpesvirus infection and for testing the ability of potential infection and for testing the ability of potential reactivation individuals. therapeutic agents to control viral reactivation in immunocompromised individuals. CD4 T cells are not required for acute control of replicating MHV-68, but are required for effective long-term highlighted the importance of CD40-CD40L interactions in 004 T cell help control. Our early work highlighted the importance of CD4O-CD4OL interactions in CD4 T cell help in the long-term control of MHV-68 and showed that CD4O stimulation alone, using agonistic that CD40 in the alone, antibodies, viral reactivation antibodies, was sufficient to prevent viral reactivation in the lungs of CD4 T cell deficient mice. cell mice. CD40 stimulation upregulates CD8O and 86 on dendritic cells, which interact with CD4O stimulation upregulates CD80 and 86 on dendritic cells, which interact with positive and and negative costimulators CD28 and CTLA-4, respectively. Interestingly, we have shown that, Interestingly, we have shown that, known CD80 and 86 are essential for long-term control of MHV-68, 0028, the although CD8O and 86 are essential for long-term control of MHV-68, CD28, the only known positive costimulatory receptor for CD80/86 is not required, suggesting the possibility of a novel required, positive costimulatory receptor for 0D80/86 superfamily, which receptor. CD28, CD8O and 86 are part of the CD28-B7 superfamily, which comprises several receptor. 0028, CD80 members that mediate positive or negative costimulation of T cells. In this application, we will members that mediate positive or negative costimulation of T cells. In this application, we will investigate the mechanisms by which CD40 and CD28-B7 family members interact to regulate investigate the mechanisms by which 0040 and CD28-B7 family members interact to regulate cell response CD8 T cell responses during the response to gammaherpesvirus infection . In Aim I we will infection. In Aim 1 we will investigate why CD4 T cells are required for the long-term control of MHV-68 , but are not required long-term control MHV-68, but are not investigate why 004 T cells (acute) control essential for short-term (acute) control of the virus. Our data suggests that two virus. alternative pathways of 008 T cell activation function alternative pathways of CD8 T cell activation function during acute, but not during long-term during long-term control. In Aim 2 we will investigate the possibility that a novel receptor for CD80/86 (B7-1, 2) control. In Aim 2 we will investigate the possibility that a novel receptor for 0D80/86 (B7-l, functions in the long-term control of MHV-68. In Aim 3, we will investigate the role of PD-1, an in control MHV-68. In Aim 3, will role PD-I, an inhibitory B7 family member that we have shown is upregulated on 008 cells in the absence of inhibitory B7 family member that we have shown is upregulated on CD8 T cells in the absence of CD4 T cells, in acute and long-term control of MHV-68. These studies will provide important 0D4 T cells, in acute and long-term control of MHV-68. These studies will provide important insight into differences in the mechanisms by which CD8 T cells mediate acute and long-term which acute and control control of persistent viral infections and may be of significant value in designing viral and in designing immunotherapeutic agents or vaccines to combat recurrent gammaherpesvirus infections Sarawar, Sally 1 c>. �-0 3,p C'(0 fl? can 0)3 CL) CSC BCD :cum ono o,-.o vo(Q chi �0= E I-- 0-0 II) 60, (00 ,�- �c' p-0 `ate.