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.

总结。疫苗接种是历史上最重要的公共卫生成就之一。然而，我们正在 仍然无法诱导对重要的人类病原体的保护性免疫，如流感。因此， 传染病仍然是致残和死亡的主要原因。一个“成功”的基本要素 疫苗是一种产生长寿浆细胞(LLPC)和记忆B细胞的能力，它们可以产生 保护性抗体(Ab)，并提供长期预防性免疫。重要的是，LLPC的发展 记忆B细胞位于生发中心(GC)。因此，了解这些机制是至关重要的。 控制GC反应的物质。然而，尽管在该领域取得了重大进展，但我们对 控制GC反应的机制仍然有限。我们知识中的一个关键差距是如何“GC” 命运的决定“是受调控的，尤其是GC B细胞如何”选择“是留在GC中还是分化 转化为高度突变的LLPC或成为记忆B细胞并离开GC。对……缺乏准确的了解 微调GC输出的机制是设计新的 克服个体病原体适应的疫苗接种策略。在这方面，以前的研究表明， 肺中预先存在的流感特异性记忆B细胞在再次感染后提供关键保护。 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 这些知识对于设计更有效的呼吸道病毒疫苗接种策略至关重要， 例如流感或SARS-CoV2。重要的是，CD4+T滤泡辅助细胞(TFH)在 促进GC B细胞反应。事实上，在没有TFH细胞的情况下，GC反应和抗体介导的保护 都受到了损害。因此，人们普遍认为，接种疫苗后TFH细胞的反应增强将 显著提高疫苗的效力。不幸的是，我们仍然不知道什么功能性质 定义一个“高质量”的TFH细胞反应。我们的初步数据表明，当免疫反应 随着病情的发展，流感特异性TFH细胞的反应会“进化”。因此，TFH细胞的不同亚群 都出现在流感感染后的不同时间。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细胞相互作用收到质的不同 信号，暂时微调GC的输出和肺记忆B细胞的产生。这个 此应用程序的长期目标是1)确定不同的TFH细胞子集在 控制内存/LLPC分化平衡。2)定义调节生成的机制 具有促进增强B细胞介导的呼吸道保护能力的“高质量”TFH细胞 病毒。3)确定控制基因产生的分子和转录机制 肺记忆B细胞和记忆/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量身定做的新疫苗接种战略至关重要。