Dendritic cell-dependent activation of B cells during immune responses

描述（由申请方提供）：免疫系统提供保护以防止复发感染的能力高度依赖于抗原（Ag）特异性继发或记忆应答。尽管次级反应具有重要的性质，但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。该提案的总体目标是更好地了解体内驱动次级Ab反应的细胞相互作用。虽然记忆B细胞通常被认为是在二次免疫应答后观察到的Ag特异性抗体滴度的快速上升，但幼稚B细胞对二次应答的贡献尚不清楚。我们的中心假设假设，树突状细胞介导的B细胞激活后，第二次抗原的挑战是至关重要的快速性质和多样性的第二抗体反应。通过采用过继转移系统，使用来自携带对半抗原特异性的靶向IG重链的小鼠的初始Ag特异性B细胞，（4-羟基-3-硝基苯基）乙酰（NP），我们将在目的1中表征初始B细胞在二次（回忆）Ag应答期间的应答，并确定其活化的要求，包括B细胞受体（BCR）对Ag的亲和力，CD 4 T细胞帮助，CD 22表达。免疫与免疫复合物增强主要抗体反应通过一个未知的机制，需要Fc？受体的骨髓来源的细胞，可能是DC。最近已经显示DC内化并将Ag直接呈递给B细胞，诱导其活化。在目的2中，我们将使用我们实验室开发的Ag特异性DC-B细胞共培养系统来确定通常在体内发现的脾DC的哪些亚群可以支持B细胞活化和分化。我们将进一步扩展这些研究，以确定在二次Ab应答期间幼稚B细胞活化是否需要DC，并测试以下假设：用含Ag DC免疫足以产生快速和/或多样的B细胞应答，这是原位发现的二次Ab应答的特征。目前使用的大多数疫苗都依赖于产生强烈和持久的抗体反应。理解导致保护性Ab应答的机制对于旨在刺激免疫系统的体液臂以产生中和Ab的疫苗的合理设计至关重要。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细胞应答，二次（或加强）免疫是疫苗接种方案经常采用的一种策略，以提高血清Ab水平。

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