Mast cell control of endogenous, antigen-specific CD4 T cell immunity

肥大细胞控制内源性抗原特异性 CD4 T 细胞免疫

基本信息

批准号：
9019796
负责人：
James B McLachlan
金额：
$ 22.58万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-19 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9019796
关键词：
Address Affect Antibodies Antibody Formation Antigen Presentation Antigens Asthma Automobile Driving B-Lymphocytes Bacteria Bone Marrow CD4 Positive T Lymphocytes Cell Count Cell physiology Cells Cessation of life Complex Conflict (Psychology)Data Development Disease Ear Elements Equilibrium Evolution Goals Health Helper-Inducer T-Lymphocyte Histocompatibility Antigens Class II Human Hypersensitivity Immune Immune response Immune system Immunity Immunization Infection Injection of therapeutic agent Interferons Interleukin-4 Investigation Knock-out Knowledge Laboratories Lead Ligation Literature Lymphoid MHC Class II Genes Maintenance Mediating Mediator of activation protein Mission Modeling Mus Organism Outcome Parasites Phenotype Physiological Play Population Production Reporting Research Research Design Role Signal Transduction Skin Skin Tissue Stimulus Surface T cell differentiation T cell response T-Cell Activation T-Lymphocyte Testing Th1 Cells Th2 Cells Therapeutic Intervention Time Tissues Vaccines Work adaptive immunity antimicrobial arm base chemokine combat cytokine human disease killings lymph nodes macrophage mast cell migration mucosal site novel pathogen public health relevance reconstitution research study response uptake

项目摘要

DESCRIPTION (provided by applicant): Mast cells have long been known to be important cellular causes of asthma and allergy. Recent studies have challenged that pathophysiological paradigm in favor of a much more diverse role for mast cells in various aspects of immunity. Conflicting reports in the literature have assigned both effector and suppressor roles to mast cells based on how they are stimulated. While it is clear that mast cells are potent innate immune cells essential for early clearance of pathogens, such as bacteria and parasites, far less is known about what role mast cells play in adaptive immunity, especially with respect to their effect on helper T cell immunity. Our preliminary experiments using major histocompatibility complex class II (MHCII) tetramers to examine mast cell effects on endogenous, antigen-specific helper CD4 T cell immunity showed that inducing mast cell degranulation in the tissue led to a significant increase in antigen-specific helper CD4 T cell numbers in draining lymph nodes. Further, we established that a lack of mast cells led to a marked decrease in antigen-specific CD4 T cell accumulation in antigen-containing tissue. These combined results, in addition to our past work, lead us to the hypothesis that mast cells contribute to endogenous helper T cell population expansion and migration and, ultimately, regulate helper T cell functional phenotypes. We further posit that this T cell activation is mediated through direct mast cell effects on CD4 T cells, including cytokine production by mast cells and that this is determined by how mast cells are initially activated. We will test this hypothesis using MHCII tetramers to analyze endogenous, antigen-specific CD4 T cells combined with mast cell deficient mice or mast cell deficient mice reconstituted with bone marrow derived mast cells. Aim 1 will examine the role for mast cells in initiating and maintaining the antigen-specific CD4 T cell response in antigen-containing tissue and antigen-draining lymph nodes while Aim 2 will assess the function of mast cells in driving CD4 T cell Th phenotypes in response to different mast cell activation stimuli. These studies are designed to examine multiple mast cell effects on antigen-specific CD4 helper T cell immunity. This investigation should provide novel opportunities to guide the response in favor of pathogen elimination leading to better mast cell based therapeutic interventions benefitting human health.

描述（由适用提供）：长期以来，肥大细胞一直是哮喘和过敏的重要细胞原因。最近的研究挑战了病理生理范式，赞成在免疫的各个方面对肥大细胞的多样性作用。文献中的报道矛盾的报告将效应子和抑制作用的作用分配给了肥大细胞，并根据其刺激方式分配给肥大细胞。虽然很明显，肥大细胞是潜在的先天免疫细胞对于早期清除病原体所必需的，例如细菌和寄生虫，但对肥大细胞在适应性免疫（and）中的作用众所周知，尤其是在其对辅助T细胞免疫的影响方面。我们使用主要的组织相容性复合物II类（MHCII）四聚体的初步实验检查对内源性细胞对内源性，抗原特异性辅助辅助辅助CD4 T细胞免疫的影响，表明，诱导的组织细胞在组织中诱导的肥大细胞脱粒，从而显着增加了抗原特异性助手CD4 T细胞数量在抑制Lymph nodes中的抗原特异性CD4 T细胞数。此外，我们确定缺乏肥大细胞导致抗原含有抗原的组织中抗原特异性CD4 T细胞的积累显着降低。除了过去的工作之外，这些结合结果除了我们过去的工作外，还提出了肥大细胞有助于内源性辅助助手T细胞种群扩展和迁移的假设，并最终调节了辅助辅助T细胞功能表型。我们进一步定位，该T细胞激活是通过直接桅杆介导的细胞对CD4 T细胞的影响，包括肥大细胞的细胞因子产生，这取决于肥大细胞最初激活的方式。我们将使用MHCII四聚体检验该假设，以分析内源性的，抗原特异性的CD4 T细胞与肥大细胞缺乏小鼠或与骨髓衍生的肥大细胞重构的肥大细胞缺陷小鼠相结合。 AIM 1将检查肥大细胞在启动和维持抗原特异性CD4 T中的作用含抗原的组织和AIM 2的抗原淋巴结中的细胞反应将评估肥大细胞在驱动CD4 T细胞TH表型中的功能，以响应不同的肥大细胞激活刺激。这些研究旨在检查对抗原特异性CD4辅助T细胞免疫的多种肥大细胞影响。这项投资应提供新的机会，以指导反应，有利于消除病原体，从而使基于肥大细胞的治疗干预措施有益于人类健康。