Mast cell regulation of CD8+ T cell responses

描述(申请人提供)：尽管肥大细胞因其在介导过敏反应的促炎过程中的作用而闻名，但包括我们在内的几个实验室的最新数据表明，肥大细胞在其他各种病理和保护性免疫反应中发挥关键作用。例如，在多发性硬化症(实验性变态反应性脑脊髓炎-EAE)和关节炎的小鼠模型中，肥大细胞是最大的疾病所必需的，也是抵抗许多细菌感染所必需的。在EAE中，肥大细胞在CD4和CD8自身反应性T细胞反应中发挥作用。来自免疫肥大细胞缺陷小鼠(W/WV)的T细胞与其野生型小鼠相比，表现出抗原特异性干扰素和IL-17的产生减少，CD44、CD11a、CD69和CD62L等激活标志物的变化减弱，并且不能有效地运输到中枢神经系统的靶组织。在这种情况下，次优的CD8T细胞反应是最显著的，可能是由于肥大细胞依赖的CD4T细胞帮助效率低下。这可能反映了肥大细胞对CD8T细胞的更直接影响。另外，肥大细胞可能通过影响树突状细胞的功能和迁移来间接改变T细胞的反应。这项应用中的实验将利用肥大细胞缺陷小鼠来测试这一假设，即肥大细胞有助于微环境的形成，该微环境利用一种具有良好特征的感染模型来控制初级和记忆的CD4和CD8 T细胞功能，该感染模型可以对淋巴细胞性脉络膜脑膜炎(LCMV)病毒表位产生强大的CD4和CD8 T细胞反应，这是对这种病毒的长期保护性免疫所必需的。了解导致强烈记忆反应的所有因素对于有效的疫苗开发至关重要。其具体目的是：1)明确肥大细胞在LCMV特异性的CD4和CD8T应答中的作用。2)检测肥大细胞对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。

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.