Regulatory T cell Modulation of Immunity to Mucosal Viral Infections

调节性 T 细胞对粘膜病毒感染免疫的调节

• 批准号: 8073590
• 负责人: Jennifer M Lund
• 金额: $ 43.56万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073590
• 关键词: Ablation; Address; Adoptive Cell Transfers; Adoptive Transfer; Affect; Antibodies; Antigens; Autoantigens; Autoimmune Diseases; Autoimmunity; Biological Models; Body Surface; Cell physiology; Cells; Clinical; Communicable Diseases; Data; Dendritic Cells; Disease Progression; Down-Regulation; Effector Cell; Experimental Models; Exposure to; Failure; Future; General Population; Generations; Goals; Herpesviridae; Human; Human Herpesvirus 2; IL2RA gene; Immune; Immune response; Immunity; Infection; Infectious Agent; Inflammatory; Influenza; Interferons; Intervention; Knock-in Mouse; Knowledge; Location; Lymphoid; Maintenance; Mediating; Memory; Mucous Membrane; Mus; Organ; Pathology; Peripheral; Phase; Play; Production; Public Health; Publishing; Regulatory T-Lymphocyte; Research; Resistance; Role; Route; Signal Transduction; Simplexvirus; Site; Specificity; Staging; Surface; System; T-Lymphocyte; Testing; Time; Tissues; Transgenes; United States; Vaccines; Viral; Virus; Virus Diseases; Virus Replication; Work; chemokine; combat; cytokine; design; diphtheria toxin receptor; fighting; genital herpes; human disease; improved; influenzavirus; migration; mouse model; mucosal site; new therapeutic target; novel; pathogen; prevent; programs; public health relevance; response; trafficking; transcription factor

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.

描述（由申请人提供）：调节性T细胞以抑制对自我抗原的免疫反应的作用而闻名，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细胞在免疫中对传染病的重要性。因此，出现了一个问题，即调节性T细胞如何参与这两个目标对人类生存如此重要的目标 - 防止对自我的损害免疫反应，同时允许产生免疫反应以与外国感染者作斗争。先前的研究表明，调节性T细胞在限制对各种感染剂的后期免疫反应中的作用，从而最大程度地减少免疫反应引起的组织损伤，同时预防或减少病原体清除率。但是，最近，我们通过修复及时运输免疫效应细胞到感染的部位来促进对生殖器疱疹 - -2（HSV-2）感染的早期免疫反应在促进生殖器疱疹 - 单纯疱疹（HSV-2）感染的早期免疫反应中的新颖而出乎意料的作用。因此，这种调节T细胞的免疫反应促进功能的意外发现随后导致了该建议中将解决的几种新工作。 具体而言，我们将首先解决调节性T细胞在对原发性挑战的免疫反应中的作用，并将其与第二种常见的粘膜感染中的作用进行比较，该作用被认为是主要的公共卫生威胁 - 流感病毒感染。我们假设Treg的作用可能会根据病原体的类型，细胞的位置，感染时间和感染途径而有所不同，因此我们希望这两个病毒系统将提供独特的机会，以比较和对比Treg在不同类型的感染中的作用，这些感染者在不同类型的感染中，这些感染具有不同的粘膜表面。其次，跟进以前的研究的工作，我们将表征调节性T细胞在粘膜病毒感染过程中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细胞在人体不同粘膜表面的各种类型的粘膜病毒感染中的作用，以及调节性T细胞可以在免疫反应的各个阶段起作用的不同作用。我们预计，从该研究计划中获得的知识将有助于产生改善粘膜病毒感染（包括疫苗）的临床干预措施。我们先前发表的工作以及该提案中介绍的初步数据表明，调节性T细胞在免疫反应中对病毒起着多种重要作用。因此，了解这些细胞在免疫反应过程中的何处和何时了解这些细胞的理解对于设计未来的疫苗至关重要，这将使调节性T细胞有效地帮助产生和维持保护性免疫反应。 公共卫生相关性：粘膜病毒感染（例如疱疹和流感）在美国和全球构成了公共卫生威胁。调节性T细胞的作用是适应性和先天免疫反应的有效负调节剂的作用，在病毒感染的情况下，尤其是粘膜感染的情况下，人们了解得很糟糕。由于粘膜暴露是一般人群遇到大多数影响公共卫生的常见病毒的途径，因此该拟议的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理解调节性T细胞在HSV和流感病毒感染和疾病进展中起作用的作用，这是促进寻找疫苗和治疗新的治疗靶标的总体目标的重要一步，以对抗粘膜病毒感染。