Antigen-driven B cell development at the follicular perimeter

滤泡周边抗原驱动的 B 细胞发育

• 批准号: 8424203
• 负责人: TIMOTHY L MANSER
• 金额: $ 7.75万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8424203
• 关键词: A/J Mouse; Antibodies; Antibody Formation; Antigen Receptors; Antigen-Presenting Cells; Antigens; B Cell Proliferation; B-Cell Development; B-Lymphocytes; Biological Models; C57BL/6 Mouse; Cell Communication; Cell Migration Pathway; Cells; Characteristics; Clonal Expansion; Data; Development; Elements; Future; Histologic; Humoral Immunities; Image; Image Analysis; Immune response; Immunity; Immunization; Immunoglobulin Class Switching; Immunoglobulin Somatic Hypermutation; Life; Light; Lymphoid; Mediating; Memory B-Lymphocyte; Modeling; Movement; Mus; Organ; Pathway interactions; Pattern; Physiological; Process; Reaction; Receptors, Antigen, B-Cell; Research Design; Resolution; Series; Site; Spleen; Staging; Structure of germinal center of lymph node; System; T-Lymphocyte; Techniques; Technology; Testing; Time; Transgenic Organisms; Travel; Vaccines; arsonate; cell motility; intravital imaging; lymph nodes; migration; multi-photon; novel; response; syndecan

DESCRIPTION (provided by applicant): During T cell dependent (TD) B cell immune responses leading to the development of humoral immunity, B cells undergo an ordered series of migratory and differentiation steps. These processes take place in secondary lymphoid organs (SLOs). Past data suggested that after first engaging antigen, B cells migrate to the border of T and B cells zones in SLOs, receive costimulation, and subsequently either migrate to the outer regions of T cell zones and become antibody forming cells (AFCs) or travel to the center of B cell follicles and nucleate the germinal center (GC) reaction, leading to development of long lived AFCs and memory B cells. Recently, we discovered a previously unrecognized step in TD B cell responses that takes place subsequent to B cell interaction with T cells at the T-B interface, and prior to the GC response in the spleen. During this stage, antigen-activated B cells are located at the perimeter of B cell follicles, opposite the T cell zone. There, they undergo rapid proliferation, but not heavy chain class switching or somatic hypermutation, and begin to acquire several characteristics of GC B cells. A more detailed mechanistic understand of the factors that drive B cells to the follicular perimeter, promote their proliferation at this ite, and regulate their subsequent migration to other sites in SLOs will require higher resolution studies of this response. The technique of multi-photon intravital imaging (MP-IVI) is ideal for this purpose but its current application for studies of this type is limited to imaging of response in mouse lymph nodes (LNs). As such, in Aim 1 we will determine if the follicular perimeter response takes place in LNs. If we find that it does, we will proceed to the real time analysis of this response using MP-IVI. If it does not, our future studies will focus on the physiological relevance of this spleen-specific response. In addition, our previous studies of the follicular perimeter response largely utilized a B cell antigen receptor (BCR) transgenic system in which, for unknown reasons, the BCR drives antigen activated B cells predominantly to enter GCs. Since the follicular perimeter response takes place subsequent to B cell costimulation by T cells, this stage may be a prerequisite for subsequent development of B cells to both short- lived AFCs, as well as GC B cells. Since our past model system was inadequate to test this hypothesis, in Aim 2 of this proposal we will using another BCR transgenic system in which antigen activated B cells are known to efficiently nucleate both short lived AFC and GC pathways. If we find that the follicular perimeter response precedes both the development of short-lived AFC and GCs, future studies will focus on the factors that may regulate the commitment of B cells participating in the follicular perimeter response to one of these two differentiative fates.

描述（由申请人提供）：在T细胞依赖（TD）B细胞免疫反应期间，导致体液免疫的发展，B细胞进行了一系列有序的迁移和分化步骤。这些过程发生在次级淋巴器官（SLO）中。 Past data suggested that after first engaging antigen, B cells migrate to the border of T and B cells zones in SLOs, receive costimulation, and subsequently either migrate to the outer regions of T cell zones and become antibody forming cells (AFCs) or travel to the center of B cell follicles and nucleate the germinal center (GC) reaction, leading to development of long lived AFCs and memory B cells. 最近，我们在TD B细胞反应中发现了先前未知的步骤，该步骤是在B细胞与T细胞在T-B界面上与T细胞相互作用后以及脾脏中GC响应之前发生的。在此阶段，抗原激活的B细胞位于B细胞卵泡的周长，与T细胞区相对。在那里，它们经历了快速的增殖，但不重链类转换或体细胞超名，并开始获得GC B细胞的几种特征。 更详细的机械理解对将B细胞驱动到卵泡周长的因素，在此促进其扩散，并调节其随后在SLO中迁移到其他地点的迁移将需要对此反应进行更高的分辨率研究。多光子内内室成像（MP-IVI）的技术是理想的选择，但目前对这种类型的研究应用仅限于小鼠淋巴结（LNS）中反应的成像。因此，在AIM 1中，我们将确定LNS中是否发生了卵泡周长反应。如果发现确实如此，我们将使用MP-IVI对此响应进行实时分析。如果不是这样，我们未来的研究将集中于这种脾脏特异性反应的生理相关性。 此外，我们先前对卵泡周长反应的研究在很大程度上利用了B细胞抗原受体（BCR）转基因系统，在这种情况下，由于未知原因，BCR驱动抗原激活的B细胞主要进入GCS。由于卵泡周长反应发生在T细胞B细胞共刺激之后发生，因此此阶段可能是随后向短细胞开发到短暂的AFC以及GC B细胞的先决条件。由于我们过去的模型系统不足以检验这一假设，因此在该提案的目标2中，我们将使用另一个BCR转基因系统，其中已知抗原活化的B细胞有效地有效地核定了短暂的AFC和GC途径。如果我们发现卵泡周边反应既先于短暂的AFC和GC的发展，否则将来的研究将集中在可能调节参与卵泡周边反应的B细胞对这两种差异化命运之一的因素上。