Dendritic Cell-Associated C-Type Lectins

描述(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)，人们知之甚少，这种中和抗体可以保护我们免受致命病毒和细菌的攻击。这项建议的主要目的是阐明长寿记忆B细胞发育所需的过程，这些B细胞是在AGS被脾树突状细胞(DC)亚群摄取后启动的。我们将明确银靶向边缘带(MZ)DC和浆细胞样树突状细胞(PDC)亚群诱导记忆B细胞发育和体液免疫的机制。本研究的目的是：1.利用抗人CLR、BDCA2和仅在pDC上表达BDCA2的转基因(TG)小鼠的单抗，在体内通过AGS靶向浆细胞样树突状细胞(DC)，明确如何调节CD4和CD8T细胞和体液免疫反应。2.明确BDCA2信号是否以及如何在体内抑制pDC产生I型干扰素，以及这种抑制是否可以改变狼疮样自身免疫性疾病的进程。3.通过体内靶向MZ DC的AGS来确定卵泡外抗体反应是如何产生的，并确定是什么信号将通过MZ DC靶向诱导的卵泡外抗体反应转变为免疫反应，从而导致GC的形成和长寿命、高亲和力的抗体。我们将研究MHC II类和CD22在MZ DC抗原靶向中的作用，并表征MZ DC激活卵泡外TEFH细胞所需的分子过程。这些研究可能导致对如何诱导和调节免疫记忆，特别是体液免疫的新见解。它们还可能有助于确定体内导致B细胞体细胞突变和亲和力成熟的途径，从而推动B细胞生物学领域的发展。拟议的研究还可能导致新的抗原靶向技术，有助于创造有效的疫苗，诱导针对H5N1大流行流感、艾滋病毒和丙型肝炎病毒等重要病原体的强大中和抗体反应。 公共卫生相关性：对大流行性流感病毒和许多其他病原体的保护性免疫是由抗体介导的，抗体可以中和感染。然而，关于如何诱导保护性反应仍有许多需要了解，事实上，许多疫苗仍然不能诱导非常强、持久的中和抗体。这项工作将导致对如何将抗原输送到免疫系统以诱导保护性抗体的新见解。

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.