DC-CD4 interactions in Th2 differentiation

CD4 T 细胞的效应功能是针对鞭虫和血吸虫等蠕虫的免疫反应所必需的。 CD4 T 细胞被造血抗原呈递细胞 (ARC)、树突状细胞、巨噬细胞和 B 细胞表达的主要组织相容性复合物 (MHC) II 类分子激活。 CD4 T 细胞依赖性寄生虫控制过程中对个体 MHC II 类阳性 APC 的具体要求尚未完全阐明。我们开发了转基因 CD11c/Abeta(b) 小鼠，其中 MHC II 类 I-Ab 表达特异性针对 DC；这种 II 类表达模式足以产生针对名义抗原的初级 Th1 反应并控制皮下利什曼原虫感染。相比之下，树突状细胞抗原呈递在 Th2 反应发展中的充分性尚不清楚。例如，B 细胞是产生针对名义抗原和寄生抗原的 Th2 反应以及控制胃肠道线虫毛虫所必需的。我们建议利用 CD11c/Abeta(b) 模型来检查 MHC II 类阳性 DC 在 Th2 应答的产生过程中向 CD4 T 细胞呈递抗原的充分性。 我们有三个具体目标。在具体目标 I 中，我们将检查 Th2 对模型抗原、卵清蛋白和血吸虫卵抗原的反应。在特定目标 II 中，我们将询问 DC 和 CD4 T 细胞之间的 II 类依赖性相互作用是否会驱动对鼠线虫感染的抵抗力。最后，我们将询问 DC 抗原呈递是否调节在对曼氏血吸虫的免疫反应过程中发生的从 Th1 到 Th2 极化的转变。这些试点实验将确定 DC 依赖性抗原呈递是否会产生针对寄生虫感染的保护性抗原特异性免疫反应，并将阐明疫苗开发中的靶标途径。

The effector functions of CD4+ T cells are required for the immune response to helminths such as Trichuris and Schistosoma. CD4+ T cells are activated by major histocompatibility complex (MHC) class II molecules expressed by the hematopoietic antigen presenting cells (ARC), dendritic cells, macrophages, and B cells. The specific requirement for individual MHC class ll-positive APCs during CD4+ T cell-dependent control of parasites has not been fully elucidated. We have developed transgenic CD11c/Abeta(b) mice in which MHC class II l-Ab expression is targeted specifically to DCs; this pattern of class II expression is sufficient for development of primary Th1 responses to nominal antigen and control of subcutaneous Leishmania infection. In contrast, the sufficiency of dendritic cell antigen presentation in the development of Th2 responses is less clear. For example, B cells are required for the generation of Th2 responses to nominal and parasitic antigens and control of the gastrointestinal nematode, Trichuris muris. We propose to utilize the CD11c/Abeta(b) model to examine the sufficiency of antigen presentation by MHC class ll-positive DCs to CD4+ T cells in the generation of Th2 responses. We have three Specific Aims. In Specific Aim I, we will examine Th2 responses to the model antigens, ovalbumin and Schistosomal egg antigen. In Specific Aim II, we will ask if class ll-dependent interactions between DC and CD4+ T cells drive resistance to Trichuris muris nematode infection. Finally, we will ask if DC antigen presentation regulates the switch from Th1 to Th2 polarization which occurs during the immune response to Schistosoma mansoni. These pilot experiments will determine if DC-dependent antigen presentation generates protective antigen-specific immune responses against parasitic infections and will elucidate pathways to target in vaccine development.