Mast cell regulation of CD8+ T cell responses

描述（由申请人提供）：虽然肥大细胞在介导过敏反应的促炎过程中的作用是最为人所知的，但包括我们在内的几个实验室的最近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关键作用。例如，肥大细胞是多发性硬化症（实验性过敏性脑脊髓炎- EAE）和关节炎的鼠模型中的最大疾病以及对许多细菌感染的抗性所必需的。在EAE中，肥大细胞对CD 4+和CD 8+自身反应性T细胞应答发挥作用。来自免疫的肥大细胞缺陷小鼠（W/Wv）的T细胞显示抗原特异性IFN？降低，IL-17的产生，包括CD 44、CD 11 a、CD 69和CD 62 L在内的活化标志物的减弱改变，以及与从其野生型同窝仔中分离的细胞相比，不能有效运输至CNS中的靶组织。在这种情况下，次优的CD 8 + T细胞应答是最显著的，可能是由于低效的肥大细胞依赖性CD 4 + T细胞帮助。这可能反映了肥大细胞对CD 8 + T细胞更直接的影响。或者，肥大细胞可以通过对树突状细胞功能和迁移的影响间接改变T细胞应答。本申请中的实验将利用肥大细胞缺陷小鼠来测试以下假设：肥大细胞有助于形成微环境，该微环境使用充分表征的感染模型来塑造控制初级和记忆CD 4+和CD 8 + T细胞功能的事件，该模型引发对淋巴细胞的强烈CD 4+和CD 8 + T细胞反应。脉络丛脑膜炎（LCMV）病毒表位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有效的疫苗开发至关重要。具体目的是：1）明确肥大细胞在LCMV特异性CD 4+和CD 8 + T细胞应答中的作用。2)探讨肥大细胞对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.