Regulatory T cell Modulation of Immunity to Mucosal Viral Infections

描述（由申请人提供）：众所周知，调节性T细胞在抑制对自身抗原的免疫反应中发挥作用，从而有助于预防自身免疫性疾病。此外，最近的工作强调了调节性T细胞在传染性疾病免疫中的重要性。因此，问题出现了，调节性T细胞如何参与这两个对人类生存如此重要的目标-防止对自身的破坏性免疫反应，同时允许免疫反应产生以对抗外来感染因子。先前的研究指出，调节性T细胞在限制对各种感染因子的晚期免疫反应中发挥作用，从而最大限度地减少免疫反应诱导的组织损伤，同时防止或减少病原体清除。然而，我们最近证明了调节性T细胞在促进对生殖器单纯疱疹-2 （HSV-2）感染的早期免疫反应中的一个新的和意想不到的作用，通过协调免疫效应细胞及时运输到感染部位，在那里它们可以对抗感染。因此，这一意想不到的调节性T细胞免疫反应促进功能的发现随后导致了几条新的工作线，将在本提案中讨论。具体来说，我们将首先讨论调节性T细胞在对生殖器HSV-2感染的原发性挑战的免疫反应中的作用，并将其与被认为是主要公共卫生威胁的第二种常见粘膜感染-流感病毒感染中的作用进行比较。我们假设Tregs的作用可以根据病原体的类型，细胞的位置，感染的时间和感染途径而变化，因此我们期望这两种病毒系统将提供一个独特的机会来比较和对比Tregs在感染不同粘膜表面的不同类型感染中的作用。其次，在我们之前研究的基础上，我们将描述在粘膜病毒感染过程中调节性T细胞调节树突状细胞功能的机制。最后，我们将确定调节性T细胞是否必须是抗原特异性的，以便对生殖器HSV-2感染作出反应。这些研究结果将有助于揭示调节性T细胞在机体不同粘膜表面各种类型的粘膜病毒感染中的作用，以及调节性T细胞在病毒免疫应答的不同阶段可能发挥的不同作用。我们期望从本研究项目中获得的知识将有助于改进粘膜病毒感染的临床干预措施，包括疫苗。我们之前发表的工作以及本提案中提出的初步数据表明，调节性T细胞在对病毒的免疫反应中起着几个重要作用；因此，了解这些细胞在免疫反应过程中的确切作用以及时间和地点，对于设计未来的疫苗至关重要，这些疫苗将使调节性T细胞有效地协助产生和维持保护性免疫反应。

DESCRIPTION (provided by applicant): Regulatory T cells are well known for their role in dampening the immune responses to self-antigens and thereby helping to prevent autoimmune disease. Additionally, recent work has highlighted the importance of regulatory T cells in immunity to infectious disease. Thus, the question arises as to how regulatory T cells can participate in both of these goals so important to human survival - preventing damaging immune responses to self while simultaneously permitting immune responses to be generated to fight foreign infectious agents. Previous studies have pointed to a role for regulatory T cells in limiting late immune responses to various infectious agents, thereby minimizing immune response-induced tissue damage while preventing or diminishing pathogen clearance. However, we recently demonstrated a novel and unexpected role for regulatory T cells in facilitating early immune responses to genital herpes simplex-2 (HSV-2) infection by orchestrating a timely trafficking of immune effector cells to the site of infection where they can fight infection. Therefore, this unexpected finding of an immune response-promoting function of regulatory T cells has subsequently led to several new lines of work that will be addressed in this proposal. Specifically, we will first address the role of regulatory T cells during the immune response to primary challenge with genital HSV-2 infection and compare this role to that during a second common mucosal infection that is considered to be a major public health threat- influenza virus infection. We hypothesize that the role of Tregs can vary depending on the type of pathogen, the location of the cells, the timing of infection, and the route of infection, and so we expect that these two viral systems will provide a unique opportunity to compare and contrast the role of Tregs during different types of infections that infect different mucosal surfaces. Secondly, following up on work from our previous studies, we will characterize the mechanisms by which regulatory T cells modulate dendritic cell function during mucosal viral infections. Finally, we will determine if regulatory T cells must be antigen-specific in order to respond to genital HSV-2 infection. Results from these studies will help to reveal the roles of regulatory T cells during various types of mucosal viral infections at different mucosal surfaces of the body, as well as the different roles that regulatory T cells could play at various phases of the immune response to viruses. We expect that knowledge gained from this research program will assist in the generation of improved clinical interventions for mucosal viral infections, including vaccines. Our previously published work as well as preliminary data presented in this proposal suggests that regulatory T cells play several important roles in the immune response to viruses; thus, gaining an understanding of exactly what these cells do as well as where and when in the course of an immune response is vital for designing future vaccines that will allow regulatory T cells to effectively assist in generating and maintaining protective immune responses.