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应答中的作用，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细胞在感染性疾病免疫中的重要性。因此，问题是调节性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，同时允许产生免疫反应以对抗外来感染因子。先前的研究已经指出了调节性T细胞在限制对各种感染因子的晚期免疫应答中的作用，从而最大限度地减少免疫应答诱导的组织损伤，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细胞在促进生殖器单纯疱疹-2（HSV-2）感染的早期免疫应答中的一种新的和意想不到的作用，该作用是通过将免疫效应细胞及时运输到感染部位来对抗感染。因此，调节性T细胞的免疫应答促进功能的这一意外发现随后导致了本提案中将解决的几个新的工作线。 具体来说，我们将首先解决调节性T细胞在生殖器HSV-2感染的主要挑战的免疫应答过程中的作用，并将此作用与被认为是主要公共卫生威胁的第二种常见粘膜感染-流感病毒感染进行比较。我们假设，Tendon的作用可以根据病原体的类型、细胞的位置、感染的时间和感染的途径而变化，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Tendon在感染不同粘膜表面的不同类型感染期间的作用。其次，在我们以前研究的基础上，我们将描述在粘膜病毒感染期间调节性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，以应对生殖器HSV-2感染。这些研究的结果将有助于揭示调节性T细胞在身体不同粘膜表面的各种类型的粘膜病毒感染期间的作用，以及调节性T细胞在对病毒的免疫应答的各个阶段可能发挥的不同作用。我们希望从这项研究计划中获得的知识将有助于产生改进的粘膜病毒感染的临床干预措施，包括疫苗。我们先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应答中起着几个重要作用;因此，在本发明中，了解这些细胞在免疫应答过程中的确切作用以及何时何地，对于设计未来的疫苗至关重要，这些疫苗将允许调节性T细胞有效地帮助产生和维持保护性免疫。应答 公共卫生相关性：疱疹和流感等粘液病毒感染在美国和世界范围内构成公共卫生威胁。调节性T细胞是适应性和先天性免疫应答的有效负调节因子，在一般病毒感染的情况下，特别是在粘膜感染的情况下，其作用知之甚少。由于粘膜暴露是普通人群接触大多数影响公共卫生的常见病毒的途径，因此这项拟议研究计划的目标是更好地了解调节性T细胞如何调节对粘膜病毒感染的免疫力。拟议的研究将有助于了解调节性T细胞在HSV和流感病毒感染和疾病进展中的作用，这是推进为疫苗和治疗寻找新的治疗靶点以对抗粘膜病毒感染的总体目标的重要一步。

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. PUBLIC HEALTH RELEVANCE: Mucosal viral infections such as herpes and influenza pose a public health threat in the United States and worldwide. A role for regulatory T cells, which are potent negative regulators of the adaptive and innate immune responses, is poorly understood in the case of viral infection in general and in the cases of mucosal infections in particular. As mucosal exposure is the route via which the general population encounters the majority of common viruses that impact public health, the goal of this proposed research program is to better understand how regulatory T cells modulate immunity to mucosal viral infections. The proposed studies will assist in understanding the role that regulatory T cells play in HSV and influenza viral infections and disease progression, an important step in advancing the overall goal of finding new therapeutic targets for vaccines and treatments to combat mucosal viral infections.