Dendritic cell-dependent activation of B cells during immune responses

免疫反应过程中 B 细胞的树突状细胞依赖性激活

• 批准号: 8098785
• 负责人: Craig Phillip Chappell
• 金额: $ 5.68万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8098785
• 关键词: Adoptive Transfer; Affinity; Antibodies; Antibody Formation; Antigen Presentation; Antigen-Antibody Complex; Antigens; B Cell Proliferation; B-Cell Activation; B-Lymphocytes; Bone Marrow; CD22 gene; CD4 Positive T Lymphocytes; Carrier Proteins; Cell Communication; Cells; Characteristics; Chickens; Coculture Techniques; Complex; Coupled; Data; Dendritic Cells; Disputes; Event; Flow Cytometry; Generations; Goals; Haptens; Heavy-Chain Immunoglobulins; Immune response; Immune system; Immunization; Immunoglobulins; Immunologic Memory; In Situ; In Vitro; Infection; Lead; Life; Mediating; Memory; Memory B-Lymphocyte; Modeling; Monitor; Mus; Nature; Process; Receptors, Antigen, B-Cell; Recurrence; Regimen; Regulation; Role; Secondary Immunization; Secondary to; Serum; Signal Transduction; Spleen; Structure of germinal center of lymph node; System; T-Independent Antigens; Testing; Time; Vaccination; Vaccine Design; Vaccines; antigen challenge; arm; in vivo; neutralizing antibody; receptor; response; time use; uptake; vaccination strategy

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

描述（由申请人提供）：免疫系统提供针对复发性感染的保护的能力高度依赖于抗原（Ag）特异性的次级反应或记忆反应。尽管次级反应具有至关重要的性质，但我们对产生如此显着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驱动体内次级抗体反应的细胞相互作用。虽然记忆 B 细胞通常被认为在二次免疫反应后 Ag 特异性抗体滴度迅速上升，但初始 B 细胞对二次反应的贡献尚不清楚。我们的中心假设假设，二次 Ag 攻击时树突状细胞介导的 B 细胞激活对于二次 Ab 反应的快速性和多样性至关重要。通过使用来自携带半抗原 (4-羟基-3-硝基苯基)乙酰基 (NP) 特异性的靶向 Ig 重链的小鼠的幼稚 Ag 特异性 B 细胞的过继转移系统，我们将在目标 1 中表征幼稚 B 细胞在二次（回忆）Ag 反应期间的反应，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。使用免疫复合物进行免疫可通过需要 Fc? 的未知机制增强初级抗体反应。骨髓来源细胞（可能是 DC）上的受体。最近显示 DC 可以内化 Ag 并将其直接呈递给 B 细胞，从而诱导其激活。在目标 2 中，我们将使用我们实验室开发的 Ag 特异性 DC-B 细胞共培养系统来确定体内通常发现的脾 DC 的哪些子集可以支持 B 细胞活化和分化。我们将进一步扩展这些研究，以确定二次抗体反应期间初始 B 细胞激活是否需要 DC，并测试以下假设：用带有 Ag 的 DC 进行免疫足以产生快速和/或多样化的 B 细胞反应，这是原位发现的二次抗体反应的特征。当今使用的大多数疫苗依赖于产生强烈且持久的抗体反应。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 B 细胞反应，这是疫苗接种方案经常采用的一种策略，以提高血清抗体水平