Functional Implications of Tfh Cell Heterogeneity after Infection

感染后 Tfh 细胞异质性的功能意义

• 批准号: 10442020
• 负责人: Andre Ballesteros-Tato
• 金额: $ 55.5万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-24 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10442020
• 关键词: 2019-nCoV; Achievement; Adjuvant; Affect; Agreement; Antibodies; Antibody Response; Antibody-mediated protection; B cell differentiation; B-Lymphocytes; CD4 Positive T Lymphocytes; Cells; Cessation of life; ChIP-seq; Collaborations; Communicable Diseases; Data; Development; Environment; Equilibrium; Generations; Genetic Transcription; Goals; Helper-Inducer T-Lymphocyte; Heterogeneity; Home; Homeostasis; Immune response; Immunity; Impairment; Individual; Infection; Influenza; Interferon Type II; Interleukin-12; Interleukin-4; Interleukin-6; Knowledge; Lung; Maintenance; Mediating; Memory; Memory B-Lymphocyte; Molecular; Mutate; Outcome; Output; Plasma Cells; Play; Population; Production; Property; Public Health; Reaction; Recording of previous events; Role; STAT1 gene; STAT6 gene; Scheme; Shapes; Signal Transduction; Structure of germinal center of lymph node; Testing; Time; Vaccination; Vaccines; base; cytokine; design; disability; experimental study; human pathogen; improved; influenza infection; influenzavirus; pandemic disease; pathogen; plasma cell differentiation; prevent; programs; prophylactic; respiratory virus; response; single-cell RNA sequencing; transcriptome sequencing; vaccination strategy; vaccine efficacy

SUMMARY. Vaccination is one of the most important public health achievements in history. However, we are still unable to induce protective immunity against important human pathogens, such as influenza. Thus, infectious diseases remain a major cause of disability and death. An essential component of a “successful” vaccine is the ability to generate long-lived plasma cells (LLPCs) AND memory B cells, which produce protective antibodies (Ab) and provide long-term prophylactic immunity. Importantly, the development of LLPCs and memory B cells occurs in the germinal center (GC). Thus, it is essential to understand the mechanisms that control the GC reaction. However, despite significant advances in the field, our understanding of the mechanisms that control the GC responses is still limited. One of the critical gaps in our knowledge is how “GC fate decisions” are regulated, particularly how GC B cells “choose” between staying in the GC to differentiate into highly mutated LLPCs or becoming memory B cells and leave the GCs. The lack of precise knowledge of the mechanisms that fine-tune the output of the GC is one of the main limitations when designing new vaccination strategies to overcome individual pathogen adaptions. In this regard, previous studies demonstrate that preexisting influenza-specific memory B cells in the lungs provide critical protection after reinfection. However, the factors that control the generation of lung memory B cell responses remain elusive. We believe this knowledge will be essential for designing more efficient vaccination strategies against respiratory viruses, such as influenza or SARS-CoV2. Importantly, CD4+ T follicular helper (Tfh) cells play a fundamental role in promoting GC B cell responses. In fact, in the absence of Tfh cells, GC responses and Ab-mediated protection are impaired. Thus, it is generally believed that an “enhanced” Tfh cell response after vaccination will significantly improve the efficacy of vaccines. Unfortunately, we still do not know what functional properties define a “high-quality” Tfh cell response. Our preliminary data demonstrate that, as the immune response progresses, the influenza-specific Tfh cell response “evolves.” As a consequence, different subsets of Tfh cells are present at different times after influenza infection. Based on our data, we hypothesize that GC B cells interacting with different “flavors” of Tfh cells at different times after infection receive qualitatively different signals, which temporarily fine-tunes the output of the GC and the generation of lung memory B cells. The long-term goals of this application are 1) To determine the role played by distinct subsets of Tfh cells in controlling the memory/LLPC differentiation balance. 2) To define the mechanisms that regulate the generation of “high quality” Tfh cells with the ability to promote enhanced B cell-mediated protection against respiratory viruses. 3) To determine the molecular and transcriptional mechanisms that control the generation of pulmonary memory B cells and the memory/LLPC differentiation balance in the GCs. We believe this knowledge will be essential for designing new vaccination strategies tailored against respiratory viruses.

概括。疫苗接种是历史上最重要的公共卫生成就之一。然而，我们是 仍然无法诱导针对重要人类病原体（例如流感）的保护性免疫力。因此， 传染病仍然是导致残疾和死亡的主要原因。 “成功”的重要组成部分 疫苗能够产生长寿命浆细胞 (LLPC) 和记忆 B 细胞，产生 保护性抗体（Ab）并提供长期的预防性免疫力。重要的是，有限责任公司的发展 记忆 B 细胞出现在生发中心 (GC)。因此，了解其机制至关重要 控制 GC 反应。然而，尽管该领域取得了重大进展，但我们对 控制 GC 响应的机制仍然有限。我们知识中的关键差距之一是“GC 命运决定”受到调节，特别是 GC B 细胞如何“选择”留在 GC 中以分化 进入高度突变的 LLPC 或成为记忆 B 细胞并离开 GC。缺乏准确的认识 微调 GC 输出的机制是设计新产品时的主要限制之一 克服个体病原体适应的疫苗接种策略。在这方面，先前的研究表明 肺部预先存在的流感特异性记忆 B 细胞在再次感染后提供了关键的保护。 然而，控制肺记忆 B 细胞反应产生的因素仍然难以捉摸。我们相信 这些知识对于设计针对呼吸道病毒的更有效的疫苗接种策略至关重要， 例如流感或 SARS-CoV2。重要的是，CD4+ 滤泡辅助 T (Tfh) 细胞在 促进 GC B 细胞反应。事实上，在没有 Tfh 细胞的情况下，GC 反应和 Ab 介导的保护 受到损害。因此，人们普遍认为，接种疫苗后“增强”的 Tfh 细胞反应将 显着提高疫苗的功效。不幸的是，我们仍然不知道什么功能特性 定义“高质量”Tfh 细胞反应。我们的初步数据表明，随着免疫反应 随着病情的进展，流感特异性 Tfh 细胞反应也会“进化”。因此，不同的 Tfh 细胞亚群 感染流感后的不同时间出现。根据我们的数据，我们假设 GC B 细胞 感染后不同时间与不同“味道”的Tfh细胞相互作用，收到的质量不同 信号，暂时微调 GC 的输出和肺记忆 B 细胞的生成。这 该应用的长期目标是 1) 确定 Tfh 细胞的不同亚群在 控制内存/LLPC 分化平衡。 2）定义调节生成的机制 “高质量”Tfh 细胞能够促进增强 B 细胞介导的呼吸道保护 病毒。 3) 确定控制产生的分子和转录机制 肺记忆 B 细胞和 GC 中的记忆/LLPC 分化平衡。我们相信这一点 知识对于设计针对呼吸道病毒的新疫苗接种策略至关重要。