Mast cell regulation of CD8+ T cell responses

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，但最近包括我们在内的几个实验室的数据表明肥大细胞在各种其他病理和保护性免疫反应中起着关键作用。例如，在多发性硬化症（实验性过敏性脑脊髓炎- EAE）和关节炎的小鼠模型中，肥大细胞是最大疾病的必需细胞，也是抵抗许多细菌感染的必需细胞。在EAE中，肥大细胞同时作用于CD4+和CD8+自身反应性T细胞反应。来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？与从野生型幼崽中分离的细胞相比，它们能够减少包括CD44、CD11a、CD69和CD62L在内的激活标记物的改变，并且无法有效地转运到中枢神经系统的靶组织。在这种情况下，次优的CD8+ T细胞反应是最显著的，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。另外，肥大细胞可能通过影响树突状细胞的功能和迁移间接改变T细胞的反应。本应用中的实验将利用肥大细胞缺陷小鼠来测试肥大细胞有助于形成控制原发性和记忆性CD4+和CD8+ T细胞功能的微环境的假设，使用具有良好特征的感染模型，该模型引发对淋巴细胞性脉络丛脑膜炎（LCMV）病毒表位的强大CD4+和CD8+ T细胞反应，这是对该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开发有效的疫苗至关重要。具体目的是：1)明确肥大细胞在lcmv特异性CD4+和CD8+ T反应中的作用。2)观察肥大细胞对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。

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.