Regulation of germinal center B cell fate choice by Hedgehog signaling

Hedgehog 信号传导调控生发中心 B 细胞命运选择

• 批准号: 10570972
• 负责人: ANN M HABERMAN
• 金额: $ 20.94万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-11 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10570972
• 关键词: Ablation; Address; Affinity; Antibody Formation; Antigen-Antibody Complex; Antigens; Apoptosis; B-Cell Antigen Receptor; B-Lymphocyte Subsets; B-Lymphocytes; Back; Cell Cycle; Cell Lineage; Cell division; Cells; Centroblast; Centrocyte; Chemicals; Clonal Expansion; Complement Receptor; Darkness; Data; Erinaceidae; Event; Family member; Fc Receptor; Flow Cytometry; Follicular Dendritic Cells; Gene Expression; Genes; Genetic Transcription; Hair follicle structure; Helper-Inducer T-Lymphocyte; Histologic; Humoral Immunities; Image; Immune response; Immunization; Immunoglobulin-Secreting Cells; Instruction; Light; Memory; Memory B-Lymphocyte; Molecular; Movement; Neighborhoods; Periodicity; Plasma Cells; Play; Population; Process; Production; Proliferating; Receptor Signaling; Regulation; Resistance; Rest; Role; SHH gene; Stromal Cells; Structure of germinal center of lymph node; T-Lymphocyte; Testing; Transition Elements; Vaccines; Variant; autocrine; cell behavior; cell type; epithelial stem cell; epithelial to mesenchymal transition; experimental study; in vivo; intestinal crypt; long term memory; migration; overexpression; pathogen; receptor; self renewing cell; self-renewal; smoothened signaling pathway; stem cell differentiation; stem cell niche; stemness

Project Summary Effective humoral immunity critically depends on the formation of germinal centers (GC) that generate high- affinity, long-lived memory and plasma cells. Within mature GCs, histologically distinct dark (DZ) and light zones (LZ) can be observed, the latter defined by the presence of a stromal cell type, follicular dendritic cells (FDCs). FDCs express high levels of complement and Fc receptors that retain immune complexed antigen. In addition to a depot of antigen, the LZ also harbors the majority of T follicular helper cells (Tfh). GC B cells undergo many rounds of cell division and profound shifts in gene expression during cycles of selective clonal expansion. The selection of LZ GC B cells with B cell receptors (BCR) of higher affinity involves antigen acquisition, BCR signaling and competition for Tfh cell contacts. After engagement and instruction by Tfh cells, LZ B cells undergo transcriptional rewiring that propels their movement to the DZ where they complete one or more cell divisions. Through a poorly understood process, DZ B cells eventually lose their propensity to remain within that zone and migrate back to the LZ as centrocytes. This iterative cyclic process ultimately results in the selective expansion of higher affinity BCR variants. In addition to their clonal self-renewal, GC B cells also give rise to long-term memory B cell and plasma cell lineages that exit the GC during maturation. The factors that regulate the cell fate choice of reactivated GC B cells are incompletely understood. Recent studies are consistent with the idea that stronger BCR signaling within the LZ promotes the plasma cell lineage while the formation of memory B cells predominates among GC B cells with BCRs of lower affinity for antigen, presumed to be the result of insufficient engagement of Tfh cells due to poor antigen acquisition and presentation. However, the role that FDC-derived factors might play in GC B cell fate choices have not been examined. The factors that regulate the cell fate choice of reactivated LZ B cells is poorly understood. We questioned whether stromal cell-derived factors influencing cell behavior in those niches could also play a role in GCs. We hypothesize that Hedgehog signaling plays a role in critical transitions during GC B cell re-activation that influence cell fate. We propose to define the Hedgehog dependent and independent events and their impact on GC B cell lineage divergence. These questions will be addressed through the inhibition or ablation of Hedgehog signaling and an examination of the effect on GC B cell self-renewal or the initiation of differentiation to alternative cell lineages within the GCs. Proposed experiments to assess the molecular impact of Hedgehog signaling include scRNAseq of GC B cells.

项目摘要 有效的体液免疫力严重取决于生成中心（GC）的形成 亲和力，长寿记忆和浆细胞。在成熟的GC中，组织学不同的黑暗（DZ）和光 可以观察到区域（LZ），后者由基质细胞类型，卵泡树突状细胞定义 （FDC）。 FDC表达了保留免疫复合抗原的高水平补体和FC受体。在 除了抗原库外，LZ还含有大多数T卵泡辅助细胞（TFH）。 GC B细胞 在选择性克隆循环中，经历了许多细胞分裂和基因表达的深刻变化 扩张。选择具有较高亲和力的B细胞受体（BCR）的LZ GC B细胞涉及抗原 TFH细胞触点的获取，BCR信号和竞争。在TFH细胞的参与和指导之后， LZ B细胞经历转录的重新布线，将其移动到DZ，在其中完成一个或 更多细胞分裂。通过鲜为人知的过程，DZ B细胞最终失去了保持的倾向 在该区域内，并作为中心细胞迁移回LZ。这种迭代的循环过程最终导致 较高亲和力BCR变体的选择性扩展。除了克隆自我更新外，GC B细胞还提供 在成熟过程中退出GC的长期记忆B细胞和浆细胞谱系。这些因素 不完全了解重新激活的GC B细胞的细胞命运选择。最近的研究是 与LZ内更强的BCR信号传导促进血浆细胞谱系的想法一致 记忆B细胞的形成主要是GC B细胞中具有较低亲和力的抗原亲和力的BCR，据推测 是由于抗原获取和表现不佳而导致TFH细胞参与不足的结果。 但是，尚未研究FDC衍生因素在GC B细胞命运选择中的作用。 对重新激活的LZ B细胞选择细胞命运选择的因素知之甚少。我们质疑 基质细胞衍生的因素是否影响这些小甲基的细胞行为也可以在GC中发挥作用。我们 假设刺猬信号传导在GC B细胞重新激活期间的临界过渡中起作用 影响细胞命运。我们建议定义刺猬依赖和独立事件及其对 GC B细胞谱系差异。这些问题将通过抑制或消融来解决 刺猬信号传导和对GC B细胞自我更新的影响或分化的启动 到GC中的替代细胞谱系。提出的实验以评估刺猬的分子影响 信号传导包括GC B细胞的SCRNASEQ。