Tissue-engineered Aged B Cell Immune Organoid to Study Antibody Secreting Cell Differentiation Trajectory

组织工程老化 B 细胞免疫类器官用于研究抗体分泌细胞分化轨迹

• 批准号: 10804886
• 负责人: Ankur Singh
• 金额: $ 32.43万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10804886
• 关键词: 3-Dimensional; Acceleration; Adjuvant; Affinity; Aging; Animal Model; Antibodies; Antibody Affinity; Antibody Response; Antigens; B cell differentiation; B-Lymphocytes; Biocompatible Materials; CDKN1A gene; Cell Communication; Cell Cycle Checkpoint Genes; Cell Differentiation process; Cell division; Cells; Cellular Metabolic Process; Chemicals; Chromatin; Coculture Techniques; Collagen; Communicable Diseases; Coupled; Data; Development; Elderly; Engineering; Enhancers; Epigenetic Process; Exhibits; Extracellular Matrix; Follicular Dendritic Cells; Gene Expression; Generations; Genes; Genetic Transcription; Goals; Helper-Inducer T-Lymphocyte; Homologous Gene; Human; Human Engineering; Humoral Immunities; Hydrogels; IRF4 gene; Immune; Immunoglobulin Class Switching; Immunoglobulin Somatic Hypermutation; Immunoglobulin-Secreting Cells; Immunology; Individual; Infection; Influenza; Kinetics; Life; Lymphoid; Lymphoid Tissue; Lysine; Maleimides; Maps; Mediating; Medicine; Methylation; Modeling; Modification; Molecular; Mus; Mutate; Nature; Organoids; Persons; Phenotype; Plasma Cells; Plasma Enhancement; Polycomb; Polyethylene Glycols; Population; Process; Proliferating; Proteins; Reaction; Regulation; Reporting; Research; Role; Signal Transduction; Stromal Cells; Structure of germinal center of lymph node; System; T-Lymphocyte; Technology; Tissue Engineering; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Work; aged; cell age; checkpoint inhibition; cytokine; differential expression; epigenome; epigenomics; high risk; histone modification; in vivo; innovation; insight; lymph nodes; migration; multidisciplinary; plasma cell differentiation; programs; promoter; rapid testing; response; senescence; single-cell RNA sequencing; transcription factor; transcriptional reprogramming; transcriptome; unpublished works

RESEARCH SUMMARY Aged individuals, who are often at higher risk of fatality in life-threatening infectious diseases, do not form high- quality antibodies against new infections. Humoral immunity against infections depends on the germinal center (GC) differentiation process in the B cell follicles of lymph nodes. In GCs, naïve B cells rapidly proliferate in response to T cell-dependent antigens and somatically mutate into high-affinity antibody-secreting cells, i.e., plasma cells. B cells assume heterogeneous cell fates upon stimulation in young mice, with only a fraction differentiating into antibody-secreting cells (ASC). Notably, plasma cell differentiation is controlled by multiple cell division-coupled epigenetic programs. Chromatin accessibility changes correlate with gene expression and reveal the reprogramming of transcriptional networks and the genes they regulate at specific cell divisions. A subset of genes in naive B cells display accessible promoters in the absence of transcription and are marked by the histone modification H3 lysine 27 trimethylation (H3K27me3), a Polycomb protein Enhancer of zeste homolog 2 (EZH2) catalyzed repressive modification. Such genes encode regulators of cell division and metabolism and include the essential plasma cell transcription factor Blimp-1. Consequently, chemical inhibition of EZH2 results in enhanced plasma cell formation. A significant concern is that with aging, B cells exhibit a decreased expansion of B cells and GC reaction in response to antigen partly due to immune senescence and a defective follicular T helper cell (TFH) system. As a result, aged mice cannot generate sufficient GCs to provide insight into ASC fate and epigenomic remodeling of GC B cells, necessitating the development of a tissue-engineered model of an aged lymph node. Therefore, the long term goal of this R01 is to develop an ex vivo “aged B cell follicle” organoid technology capable of inducing early GC programming of aged B cells from both mice and humans and enabling the study of plasma cell fate and regulation of the epigenome of B cells to identify checkpoint targets that can be suppressed to boost GC response in aged B cells. The R01 brings together a multidisciplinary team of experts in GC organoids, vaccine, adjuvants, and lymphoid tissue engineering (Ankur Singh, PI, Georgia Tech) and GC immunology, ASC fate mapping and epigenomics (Jeremy Boss, Co-I, Emory Medicine), and microenvironment spatial omics (Ahmet Coskun, Co-I, Georgia Tech).

研究摘要 老年人通常在威胁生命的传染病中患死亡的风险较高，不会形成高 针对新感染的质量抗体。对感染的体液免疫取决于生发中心 （GC）淋巴结B细胞福里的分化过程。在GC中，幼稚的B细胞在 对T细胞依赖性抗原的反应，并体形突变为高亲和力分泌细胞，即 浆细胞。 B细胞在年轻小鼠中刺激时假设异质细胞命运，只有一小部分 区分分泌抗体分泌细胞（ASC）。值得注意的是，浆细胞分化由多个控制 细胞分裂耦合表观遗传程序。染色质的可及性的变化与基因表达和 揭示转录网络的重编程及其在特定细胞分裂处调节的基因。一个 幼稚B细胞中基因的子集在没有转录的情况下显示出可访问的启动子，并以 组蛋白修饰H3赖氨酸27三甲基化（H3K27me3），一种Zeste同源物的多肉液蛋白增强剂 2（EZH2）催化反射性修饰。这些基因编码细胞分裂和代谢的调节因子以及 包括必需的浆细胞转录因子Blimp-1。因此，化学抑制EZH2结果 在增强的浆细胞形成中。一个重要的问题是，随着衰老，B细胞表现出降低的膨胀 B细胞和GC对抗原反应的反应部分是由于免疫感应和缺陷的滤泡T 辅助电池（TFH）系统。结果，老年小鼠无法产生足够的GC来洞悉ASC命运 GC B细胞的表观基因组重塑，对于开发了开发的组织模型的发展 老年淋巴结。因此，该R01的长期目标是开发一个离体“老化B细胞叶状器官”类器官 能够诱导小鼠和人类的老年B细胞的早期GC编程的技术，并启用 血浆细胞命运和B细胞表观基因组的调节，以识别可以是的检查点靶标 在老化的B细胞中抑制以增强GC反应。 R01汇集了一个多学科的专家团队 在GC器官中，疫苗，调节器和淋巴组织工程（Ankur Singh，Pi，Georgia Tech）和GC 免疫学，ASC脂肪图和表观基因组学（Jeremy Boss，Co-I，Emory Medicine）和微环境 空间上的OMICS（Ahmet Coskun，Co-I，佐治亚理工学院）。