Dendritic cell-dependent activation of B cells during immune responses

描述（由申请人提供）：免疫系统对复发性感染提供保护的能力高度依赖抗原（Ag）特异性继发反应或记忆反应。尽管次要反应的关键性质，我们对产生如此显著结果的相互作用和信号事件知之甚少。该建议的总体目标是更好地理解驱动体内继发性Ab反应的细胞相互作用。虽然记忆B细胞通常被认为与继发性免疫反应后ag特异性抗体滴度的快速上升有关，但幼稚B细胞对继发性免疫反应的贡献尚不清楚。我们的中心假设假设树突状细胞介导的B细胞在继发性Ag挑战下的激活对继发性Ab反应的快速性质和多样性至关重要。通过采用过继性转移系统，使用携带半抗原（4-羟基-3-硝基）乙酰基（NP）靶向Ig重链的小鼠幼稚B细胞，我们将在Aim 1中表征幼稚B细胞在继发（回忆）Ag反应中的反应，并确定其激活的要求，包括B细胞受体（BCR）对Ag的亲和力、CD4 T细胞帮助和CD22表达。免疫复合物免疫通过一种未知的机制增强初级抗体反应，需要Fc？受体在骨髓来源的细胞上，可能是树突细胞。最近有研究表明，树突状细胞内化并将银直接呈递给B细胞，诱导其活化。在目标2中，我们将使用我们实验室开发的Ag特异性DC-B细胞共培养系统，确定通常在体内发现的脾dc亚群可以支持B细胞激活和分化。我们将进一步扩展这些研究，以确定在继发性Ab反应中是否需要dc来激活初始B细胞，并验证携带ag的dc免疫足以产生快速和/或多样化的B细胞反应的假设，这些反应是原位发现的继发性Ab反应的特征。目前使用的大多数疫苗依赖于产生强烈和持久的抗体反应。了解导致保护性抗体反应的机制对于合理设计旨在刺激免疫系统体液臂产生中和抗体的疫苗至关重要。本提案中的研究将有助于我们了解二次（或加强）免疫后的B细胞反应，这是一种通常用于疫苗接种方案的策略，以提高高水平的血清抗体

DESCRIPTION (provided by applicant): The ability of the immune system to provide protection from recurrent infection is highly dependent upon antigen (Ag)-specific secondary, or memory, responses. Despite the critical nature of secondary responses, we know little about the interactions and signaling events that produce such a remarkable result. The overall goal of this proposal is to better understand the cellular interactions that drive secondary Ab responses in vivo. While memory B cells are typically accredited with the rapid rise in Ag-specific antibody titers seen following secondary immune responses, the contribution of naive B cells to the secondary response is unclear. Our central hypothesis postulates that dendritic cell-mediated B cell activation upon secondary Ag challenge is critical to the rapid nature and diversity of secondary Ab responses. By employing an adoptive transfer system using naive Ag-specific B cells from mice carrying a targeted Ig heavy chain specific for the hapten (4-hydroxy-3-nitropheny)acetyl (NP), we will characterize in Aim 1 the response of naive B cells during secondary (recall) Ag responses, and determine the requirements for their activation including B cell receptor (BCR) affinity for Ag, CD4 T cell help, and CD22 expression. Immunization with immune complexes enhances primary Ab responses through an unknown mechanism that requires Fc? receptors on bone marrow-derived cells, possibly DCs. DCs have recently been shown to internalize and present Ag directly to B cells, inducing their activation. In Aim 2, we will determine which subsets of splenic DCs normally found in vivo can support B cell activation and differentiation using an Ag- specific DC-B cell co-culture system developed in our lab. We will further extend these studies to determine whether DCs are required for naive B cell activation during secondary Ab responses, and test the hypothesis that immunization with Ag-bearing DCs is sufficient to produce the rapid and/or diverse B cell responses that are characteristic of secondary Ab responses found in situ. The majority of vaccines in use today rely upon the generation of strong and long-lasting antibody responses. Understanding the mechanisms that lead to protective Ab responses are critical for the rational design of vaccines aimed at stimulating the humoral arm of the immune system to produce neutralizing Ab. The studies in this proposal will contribute to our knowledge of B cell responses following secondary (or booster) immunizations, a strategy often employed by vaccination regimens to raise high levels of serum Ab