DC-CD4 interactions in Th2 differentiation

对鞭虫和血吸虫等蠕虫的免疫应答需要CD4T细胞的效应器功能。CD4T细胞由造血抗原提呈细胞(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体(MHC)II类分子激活。在依赖CD4T细胞控制寄生虫的过程中，对单个MHCⅡ类阳性APC的特殊要求还没有完全阐明。我们已经建立了CD11c/Abeta(B)转基因小鼠，在其中MHC II类L抗体的表达是针对DC的；这种II类表达模式足以发展对名义抗原的初级Th1反应和控制皮下利什曼原虫感染。相比之下，树突状细胞抗原提呈在Th2反应发展中的充分性还不是很清楚。例如，B细胞是产生对标称和寄生虫抗原的Th2反应以及控制胃肠道线虫Trichuris Muris的必需细胞。我们建议利用CD11c/Abeta(B)模型来检测在产生Th2反应中MHC 11阳性DC向CD4T细胞递呈抗原的充分性。 我们有三个具体目标。在特定的目标I中，我们将检测Th2对模型抗原、卵清蛋白和血吸虫卵抗原的反应。在特定的目标II中，我们将询问DC和CD4T细胞之间依赖于类11的相互作用是否推动了对旋毛虫线虫感染的抵抗力。最后，我们将询问DC抗原提呈是否调节在对曼氏血吸虫的免疫反应中发生的从Th1到Th2极化的转换。这些先导性实验将确定DC依赖的抗原提呈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，并将阐明疫苗开发的靶向途径。

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.