Mast cell regulation of CD8+ T cell responses

肥大细胞对 CD8 T 细胞反应的调节

• 批准号: 7487513
• 负责人: Melissa A Brown
• 金额: $ 18.52万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7487513
• 关键词: Allergic; Antigens; Arthritis; Attenuated; Bacterial Infections; CD4 Positive T Lymphocytes; CD44 gene; CD8B1 gene; Cell Maturation; Cell physiology; Cells; Data; Dendritic Cells; Disease; Employee Strikes; Epitopes; Event; Exhibits; Experimental Autoimmune Encephalomyelitis; Immune response; Immunity; Infection; Inflammatory; Interferons; Interleukin-17; Laboratories; Lead; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Mediating; Memory; Modeling; Multiple Sclerosis; Mus; Pathologic; Process; Production; Regulation; Resistance; Role; SELL gene; Shapes; T-Lymphocyte; Testing; Tissues; Virus; autoreactive T cell; mast cell; migration; research study; response; trafficking; vaccine development

DESCRIPTION (provided by applicant): Although mast cells are best known for their role in the pro-inflammatory processes that mediate allergic responses, recent data from several laboratories including ours have implicated mast cells as critical players in a variety of other pathologic and protective immune responses. For example, mast cells are required for maximal disease in murine models of multiple sclerosis (Experimental allergic encephalomyelitis - EAE) and arthritis and for resistance to many bacterial infections. In EAE, mast cells exert their effects on both CD4+ and CD8+ autoreactive T cell responses. T cells derived from immunized mast cell-deficient mice (W/Wv) exhibit reduced antigen-specific IFN?, IL-17 production, attenuated alterations in activation markers including CD44, CD11a, CD69 and CD62L as well as an inability to efficiently traffic to the target tissues in the CNS when compared with cells isolated from their wild type littermates. In this setting, the sub-optimal CD8+ T cell response was most striking and may be due to inefficient mast cell-dependent CD4+ T cell help. It may reflect a more direct influence of mast cells on CD8+ T cells. Alternatively, mast cells may indirectly alter T cell responses through effects on dendritic cell function and migration. Experiments in this application will utilize mast cell-deficient mice to test the hypothesis that mast cells contribute to a microenvironment that shapes events governing primary and memory CD4+ and CD8+ T cell function using a well characterized infection model that elicits robust CD4+ and CD8+ T cell responses to lymphocytic choriomeningitis (LCMV) virus epitopes that are necessary for long-term protective immunity to this virus. Understanding all of the factors that lead to a strong memory response is essential for effective vaccine development. The specific aims are: 1) To define the roles of mast cells in LCMV-specific CD4+ and CD8+ T responses. 2) To examine the influence of mast cells on dendritic cell maturation, migration and T cell stimulatory function in LCMV-infected mice.

描述（由申请人提供）：尽管肥大细胞以其在介导过敏反应的促炎过程中的作用而闻名，但来自包括我们的几个实验室的最新数据将肥大细胞与其他各种病理和保护性免疫反应中的关键参与者表示。例如，在多发性硬化症（实验性过敏性脑脊髓炎 - EAE）和关节炎以及对许多细菌感染的耐药性的鼠模型中，肥大细胞是最大疾病所必需的。在EAE中，肥大细胞对CD4+和CD8+自动反应性T细胞反应的影响发挥作用。源自免疫肥大细胞缺陷小鼠（W/WV）的T细胞表现出抗原特异性IFN？，IL-17的产生，激活标记的减弱变化，包括CD44，CD11A，CD69和CD62L，以及与CN中与CN相比，与它们的野外类型相比，无法有效地与CN的目标组织交流。在这种情况下，最佳的CD8+ T细胞反应最为惊人，可能是由于效率低下的肥大细胞依赖性CD4+ T细胞的帮助。它可能反映出肥大细胞对CD8+ T细胞的更直接影响。或者，肥大细胞可能通过对树突状细胞功能和迁移的影响间接改变T细胞反应。 Experiments in this application will utilize mast cell-deficient mice to test the hypothesis that mast cells contribute to a microenvironment that shapes events governing primary and memory CD4+ and CD8+ T cell function using a well characterized infection model that elicits robust CD4+ and CD8+ T cell responses to lymphocytic choriomeningitis (LCMV) virus epitopes that are necessary for long-term protective对该病毒的免疫力。了解导致强大记忆力反应的所有因素对于有效的疫苗开发至关重要。具体目的是：1）定义肥大细胞在LCMV特异性CD4+和CD8+ T响应中的作用。 2）检查肥大细胞对LCMV感染小鼠的树突状细胞成熟，迁移和T细胞刺激功能的影响。