Dendritic Cell-Associated C-Type Lectins

描述（由申请人提供）：令人惊讶的是，关于抗原（Ags）如何进入免疫系统并诱导B细胞产生持续水平的中和抗体（Abs），保护我们免受致命病毒和细菌的侵害，我们知之甚少。本研究的主要目标是阐明长寿命记忆B细胞发育所需的过程，该过程是在Ags被脾树突状细胞（DC）亚群摄取后启动的。我们将明确Ag靶向边缘区DC （MZ）和浆细胞样DC （pDC）亚群诱导记忆B细胞和体液免疫发育的机制。我们的目标是：1；利用Ags偶联人类CLR、BDCA2和仅在pDCs上表达BDCA2的转基因（Tg）小鼠的单克隆抗体（mab），在体内将Ags靶向浆细胞样DCs，从而确定如何调节CD4和CD8 T细胞和体液免疫应答。2. 定义体内BDCA2信号是否以及如何抑制pDCs产生I型IFN，以及这种抑制是否可以改变狼疮样自身免疫性疾病的病程。和3。为了确定在体内将Ags靶向MZ DC是如何产生滤泡外抗体反应的，并确定哪些信号将MZ DC靶向诱导的滤泡外抗体反应转变为导致GC形成和长寿命、高亲和力抗体的免疫反应。我们将研究MHC II类和CD22在基于MZ DC的Ag靶向中的作用，并表征MZ DC激活滤泡外TEFH细胞所需的分子过程。这些研究可能为如何诱导和调节免疫记忆，特别是体液免疫提供新的见解。它们还可以通过帮助定义导致B细胞体细胞突变和亲和成熟的体内途径来帮助推进B细胞生物学领域。拟议的研究还可能导致新的Ag靶向技术，用于创建有效的疫苗，这些疫苗可诱导针对H5N1大流行性流感、艾滋病毒和丙型肝炎病毒等重要病原体的强中和抗体反应。

DESCRIPTION (provided by applicant): Surprisingly little is known about how antigens (Ags) enter the immune system and induce B cells to produce sustained levels of neutralizing antibodies (Abs), which protect us against deadly viruses and bacteria. The major goal of this proposal is to elucidate processes required for the development of long-lived memory B cells, which are initiated after Ags are taken up by splenic dendritic cell (DC) subsets. We will define the mechanisms by which Ag targeting to marginal zone (MZ) DC and plasmacytoid DC (pDC) subsets induce the development of memory B cells and humoral immunity. Our Aims are: 1. To define how to regulate CD4 and CD8 T cell and humoral immune responses by targeting Ags to plasmacytoid DCs in vivo using Ags coupled to monoclonal antibodies (mAbs) specific for the human CLR, BDCA2 and transgenic (Tg) mice expressing BDCA2 only on pDCs. 2. To define if and how BDCA2 signaling inhibits type I IFN production by pDCs in vivo and whether this inhibition can alter the course of a lupus-like autoimmune disease. And 3. To define how extrafollicular Ab responses are generated by targeting Ags to MZ DCs in vivo and define what signals shift extrafollicular Ab responses induced via MZ DC targeting into an immune response leading to GC formation and long-lived, high-affinity Abs. We will investigate the role of MHC class II and CD22 in MZ DC-based Ag targeting and characterize the molecular processes required for MZ DCs to activate extrafollicular TEFH cells. These studies may lead to new insights into how to induce and regulate immunologic memory, and in particular humoral immunity. They may also help advance the field of B cell biology by helping to define the in vivo pathways leading to somatic mutation in B cells and affinity maturation. The proposed studies also may lead to new Ag targeting technology useful for the creation of effective vaccines which induce strong neutralizing antibody responses against important pathogens like H5N1 pandemic FLU, HIV, and hepatitis C viruses. PUBLIC HEALTH RELEVANCE: Protective immunity to pandemic influenza viruses and many other pathogens is mediated particularly by antibodies, which neutralize the infection. However, much remains to be learned about how to induce protective responses, and indeed, many vaccines still do not induce very strong, long-lasting neutralizing antibodies. This work will lead to new insights into how to deliver antigens into the immune system so that protective antibodies are induced.