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: 7393034
• 负责人: Melissa A Brown
• 金额: $ 22.65万
• 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/7393034
• 关键词: Allergic; Antigens; Arthritis; Attenuated; Autoimmune Diseases; Bacterial Infections; Biological Models; CD4 Positive T Lymphocytes; CD44 gene; CD8B1 gene; Cell Differentiation process; Cell Maturation; Cell physiology; Cell surface; Cells; Class; Data; Dendritic Cells; Dendritic cell activation; Disease; Employee Strikes; Epitopes; Event; Exhibits; Experimental Autoimmune Encephalomyelitis; Experimental Models; Histamine; Immune response; Immunity; Infection; Inflammatory; Interferons; Interleukin-17; Interleukin-4; Kinetics; Laboratories; Lead; Life; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Mediating; Mediator of activation protein; Memory; Modeling; Multiple Sclerosis; Mus; Pathologic; Peptides; Process; Production; Prostaglandins; Regulation; Resistance; Rheumatoid Arthritis; Role; SELL gene; Shapes; T memory cell; T-Lymphocyte; TNF gene; TNFRSF5 gene; TNFSF5 gene; Testing; Tissues; Viral; Virus; Virus Diseases; autoreactive T cell; in vivo; 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）：虽然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，但包括我们在内的多个实验室的最新数据表明，肥大细胞在各种其他病理性和保护性免疫反应中发挥着关键作用。例如，多发性硬化症（实验性过敏性脑脊髓炎 - EAE）和关节炎小鼠模型中的最大疾病以及对许多细菌感染的抵抗力都需要肥大细胞。在 EAE 中，肥大细胞对 CD4+ 和 CD8+ 自身反应性 T 细胞反应发挥作用。与从野生型同窝小鼠中分离的细胞相比，来自免疫的肥大细胞缺陷小鼠 (W/Wv) 的 T 细胞表现出抗原特异性 IFNα、IL-17 产生减少，激活标记物（包括 CD44、CD11a、CD69 和 CD62L）的改变减弱，以及无法有效运输到 CNS 中的靶组织。在这种情况下，次优的 CD8+ T 细胞反应最为引人注目，可能是由于肥大细胞依赖性 CD4+ T 细胞帮助效率低下。这可能反映了肥大细胞对CD8+T细胞更直接的影响。或者，肥大细胞可能通过影响树突状细胞功能和迁移来间接改变 T 细胞反应。本申请中的实验将利用肥大细胞缺陷型小鼠来测试以下假设：肥大细胞有助于塑造控制初级和记忆 CD4+ 和 CD8+ T 细胞功能事件的微环境，使用特征明确的感染模型，引发对淋巴细胞性脉络膜脑膜炎 (LCMV) 病毒表位的强烈 CD4+ 和 CD8+ T 细胞反应，这是长期保护所必需的。 对这种病毒有免疫力。了解导致强烈记忆反应的所有因素对于有效开发疫苗至关重要。具体目标是： 1) 明确肥大细胞在 LCMV 特异性 CD4+ 和 CD8+ T 反应中的作用。 2)考察肥大细胞对LCMV感染小鼠树突状细胞成熟、迁移和T细胞刺激功能的影响。