Signaling and Selection in Germinal Center B Cells

生发中心 B 细胞的信号传导和选择

• 批准号: 9017907
• 负责人: MARK J SHLOMCHIK
• 金额: $ 38.1万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9017907
• 关键词: Affect; Affinity; B-Lymphocytes; Biology; CD22 gene; Cell Cycle; Cell Lineage; Cell Survival; Cells; Cytoplasmic Tail; Event; Evolution; G2 Phase; Gene Expression; Generations; Genes; Goals; Health; Heterogeneity; Humoral Immunities; ITAM; Immune response; Immune system; Immunization; Immunoglobulin G; Immunoglobulin M; In Vitro; Individual; Infection; Investigation; Kinetics; Life; Ligands; Ligation; Link; Mediating; Memory; Memory B-Lymphocyte; Molecular; Nature; Outcome; PTPN6 gene; Phosphoric Monoester Hydrolases; Physiological; Plasma Cells; Positioning Attribute; Process; Reaction; Receptor Signaling; Receptors, Antigen, B-Cell; Regulation; Resistance; Signal Pathway; Signal Transduction; Somatic Mutation; Source; Specificity; Structure; Structure of germinal center of lymph node; T-Lymphocyte; Testing; Time; Translation Alteration; Vaccination; Vaccines; Work; cell type; functional outcomes; in vivo; insight; mutant; pathogen; plasma cell development; receptor function; response

DESCRIPTION (provided by applicant): The germinal center (GC) is a primary source of long-lived memory B and plasma cells (PCs). Affinity maturation, somatic mutation, and generation of intraclonal diversity are all key processes that occur in the GC, with the net result dramatically affecting humoral immunity to both pathogens and vaccines. Despite recent progress, the mechanisms behind central processes including selection for higher affinity, selection against self-reactivity, and control of decisions to differentiate into memory or PC lineages remain unresolved. This proposal focuses on selection and signaling in the GC. Recently, during investigations of B cell receptor (BCR) function in the GC, we were surprised to find that classical BCR signal transduction was all but extinguished in the vast majority of GC B cells (GCBC). This was in large part mediated by increased functional phosphatase activity. However, we found that GCBC were relieved of suppression and able to signal again when reaching the G2 phase of cell cycle. These findings not only provided fresh insights into how Ag might guide the fate of B cells in the GC, they also highlighted how little we yet know about BCR signaling and function during physiologic immune responses and in cell types other than na¿ve B cells. In particular, GCBC massively remodel gene expression and these shifts combined with many post-transcriptional/translation alterations could greatly influence signaling pathways and outcomes. We are now in a position to more deeply elucidate the extent and nature of BCR signaling in the GC and to understand the implications and mechanisms of GC B cell selection. Here we propose to further explore and define BCR signaling in the GC. These studies will inform our understanding of both BCR signaling and GC biology at a basic level. Through this work, we hope to link molecular events in the GCBC with functional outcomes, with the long-term goal of developing a detailed understanding of selection at both the molecular and cellular levels. We will pursue this long-term goal via three Aims. The first is focused on defining the limits and parameters of inactivation of BCR signal transduction in the GC, as well as in non-GC activated B cells. The second seeks to understand how selection works by testing the outcome of BCR and T cell signals on GCBC. The final aim tests hypotheses about GCBC signaling per se, with a goal of beginning to elucidate how GC BCR signaling is rewired compared to na¿ve B cells.

描述（由申请人提供）：生发中心（GC）是长寿记忆B和浆细胞（PC）的主要来源。亲和力成熟、体细胞突变和克隆内多样性的产生都是GC中发生的关键过程，其最终结果显著影响了对病原体和疫苗的体液免疫。尽管最近的进展，中央过程背后的机制，包括选择更高的亲和力，选择对自我反应性，并控制决定分化为记忆或PC谱系仍然没有解决。这个建议集中在GC中的选择和信令。近年来，在研究B细胞受体（BCR）在胃癌中的功能时，我们惊奇地发现，经典的BCR信号转导在绝大多数胃癌B细胞（GCBC）中几乎消失。这在很大程度上是由功能性磷酸酶活性增加介导的。然而，我们发现GCBC在达到细胞周期的G2期时被解除抑制并能够再次发出信号。这些发现不仅为Ag如何引导GC中B细胞的命运提供了新的见解，而且还强调了我们对生理免疫应答期间和幼稚B细胞以外的细胞类型中的BCR信号传导和功能知之甚少。特别是，GCBC大规模重塑基因表达，这些变化与许多转录后/翻译改变相结合，可以极大地影响信号通路和结果。我们现在能够更深入地阐明GC中BCR信号传导的程度和性质，并理解GC B细胞选择的含义和机制。在这里，我们建议进一步探索和定义GC中的BCR信号。这些研究将为我们了解BCR信号传导和GC生物学提供基础。通过这项工作，我们希望将GCBC中的分子事件与功能结果联系起来，长期目标是在分子和细胞水平上详细了解选择。我们将通过三个目标来实现这一长期目标。第一个重点是确定GC和非GC激活的B细胞中BCR信号转导失活的限度和参数。第二个试图通过测试GCBC上BCR和T细胞信号的结果来了解选择是如何起作用的。最终的目的是测试关于GCBC信号本身的假设，目的是开始阐明GC BCR信号与幼稚B细胞相比如何重新连接。