Storage and recall of human B cell memory of influenza over tissues and time

项目摘要 每个个体在接种疫苗后或接种后会引起不同B细胞克隆谱系的多样化和复杂性混合 感染，其中一些保留为记忆B细胞或浆细胞。然而，两国之间的关系 抗体的特异性和亲和力决定哪些B细胞系持续存在，哪些细胞隔间 占领运动，以及他们未来能够识别哪些抗原还不太清楚。详细分子 了解导致老年人疫苗反应下降的变化也是一个难以实现的目标。我们 旨在通过对健康的年轻人和老年人进行为期5年的纵向队列研究来克服这些障碍 接种季节性流感疫苗的人类受试者以及一群已故的器官捐赠者 对他的脾、淋巴结、骨髓和血液进行采样。我们将比较抗体谱系 与血液相比，在记忆B细胞库中发现的流感特异性细胞的结合特异性 纵向队列中的浆母细胞和CD71+活化的B细胞亚群，以及记忆B细胞 与器官捐献者的骨髓浆细胞(BMPC)池进行比较。 通过研究抗体谱系未突变祖先的流感血凝素(HA)特异性，以及 突变的记忆B细胞、浆母细胞、活化的B细胞和BMPC后代，我们将确定： 哪种体细胞突变改变了克隆血统中后来成员的HA特异性；未来的疫苗 反应可以从个体的记忆B细胞池中预测出来；BMPC是否受到不同的 选择标准比记忆B细胞在淋巴结、脾和血液中的影响；以及对人体的影响 衰老对体液免疫的每一个关键成分都有影响。这些知识将有助于制定战略。 用于改进的流感疫苗，以及针对新疫苗的所有新病原体 需要被开发。

Project Summary Each individual elicits a diverse and complex mixture of different B cell clonal lineages after vaccination or infection, some of which are retained as memory B cells or plasma cells. However, the relationships between antibody specificity and affinity in determining which B cell lineages persist, which cellular compartments they occupy, and what future antigens they are able to recognize are not well understood. Detailed molecular understanding of the changes that decrease vaccine responses in old age has also been an elusive goal. We aim to overcome these barriers by studying a 5-year longitudinal cohort of healthy young adult and elderly human subjects vaccinated with seasonal influenza vaccine, as well as a cohort of deceased organ donors whose spleen, lymph nodes, bone marrow, and blood are sampled. We will compare the antibody repertoires and binding specificities of influenza-specific cells found in memory B cell pools compared to blood plasmablasts and a distinct CD71+ subset of “activated B cells” in the longitudinal cohort, and memory B cells in lymph nodes and spleen compared to bone marrow plasma cell (BMPC) pools in the organ donors. By studying the influenza hemagglutinin (HA) specificity of unmutated ancestors of antibody lineages, and the mutated memory B cell, plasmablast, activated B cell and BMPC progeny, we will determine: the extent to which somatic mutation alters the HA specificity of later members of the clonal lineage; whether future vaccine responses can be predicted from an individual's memory B cell pool; whether BMPCs are subject to different selection criteria than the memory B cells in the lymph nodes, spleen and blood; and the impact of human aging on each of these critical components of humoral immunity. This knowledge will help to shape strategies for improved vaccines for influenza, as well as the whole range of emerging pathogens for which new vaccines need to be developed.