Induction of bronchus-associated lymphoid tissue is an early life adaptation for promoting human B cell immunity

Infants and young children are more susceptible to common respiratory pathogens compared to adults, but can fare better against novel pathogens like SARS-CoV-2. The mechanisms by which infants and young children mount effective responses to respiratory pathogens are unknown. Here, we demonstrate through study of lungs and lung-associated lymph nodes (LLN) from infant and pediatric organ donors, aged 0-13 years, that bronchus-associated lymphoid tissue (BALT), develops in lungs during the first year of life. BALT structures, consisting of B cell follicles and T cell zones, increase in numbers in the early years, and subsequently decrease over childhood coincident with accumulation of memory T cells in the lung. Early life BALT contains germinal centers and supports B cell differentiation, clonal expansion, somatic hypermutation, and immunoglobulin class switching. High dimensional flow cytometry reveals seeding of lungs by newly formed B cells (transitional cells) during infancy coincident with the timing of maximal BALT formation. We further demonstrate increased lung-localized B cell responses during respiratory virus infection in infants. Together, our findings provide novel evidence for BALT as an early life adaptation for mobilizing in situ immune protection to the diverse respiratory challenges during this formative life stage.

与成人相比，婴幼儿更易感染常见呼吸道病原体，但对新型冠状病毒（SARS-CoV-2）等新发病原体的耐受情况更佳。目前学界尚未明确婴幼儿针对呼吸道病原体启动有效免疫应答的具体机制。本研究通过对0至13岁婴幼儿及儿童器官捐赠者的肺脏与肺相关淋巴结（lung-associated lymph nodes, LLN）开展分析，证实支气管相关淋巴组织（bronchus-associated lymphoid tissue, BALT）会在生命的第一年于肺内发育形成。由B细胞滤泡与T细胞区构成的支气管相关淋巴组织结构，在生命早期数量逐步增加，随后在儿童期随肺内记忆T细胞的积累而逐渐减少。生命早期的支气管相关淋巴组织含有生发中心，可支持B细胞分化、克隆扩增、体细胞超突变以及免疫球蛋白类别转换。高维流式细胞术分析显示，在婴幼儿阶段，新形成的B细胞（过渡型B细胞，transitional cells）会定植于肺脏，这一时段与支气管相关淋巴组织形成的峰值时间相吻合。我们还证实，婴幼儿在呼吸道病毒感染期间，肺内局部B细胞应答水平会有所升高。综上，本研究结果为支气管相关淋巴组织作为生命早期的适应性免疫结构，可针对该发育阶段内的多种呼吸道挑战调动原位免疫保护提供了全新证据。