Human airway epithelial B-cell activating factor is reduced in early life but is virally induced via JAK/STAT

Background: Early infancy is marked by high susceptibility to severe viral respiratory infections and reduced protective antibody responses, making rapid development of local airway immunity essential. Despite this, the developmental dynamics of human airway B cells and their interaction with airway epithelial cells (AECs) in early life remain poorly understood. Objective: We studied the developmental dynamics of human airway B-cell populations, the variation in AEC-derived B-cell survival and maturation factors with age, and how viral respiratory infections influence their production. Methods: Changes in human airway B-cell populations and survival receptors across different pediatric age groups were analyzed by using a single-cell RNA sequencing dataset. The production of B-cell activating factor (BAFF) and other B-cell survival and maturation factors by human AECs was assessed in infants (<12 months) and older children, both at baseline and after viral stimulation in vitro. Additional in vivo validation studies assessed airway BAFF production at baseline and during PCR-confirmed viral respiratory infections across pediatric age groups. Results: We observed age-dependent shifts in airway B-cell composition, identifying the BAFF/BAFF-receptor axis as critical for B-cell maturation and survival in early life. Although BAFF production in AECs is initially reduced in infants (<12 months), it can be activated by viral stimuli both in vivo and in vitro. Mechanistic studies showed that BAFF production in human infant AECs is induced by type I and III interferons via JAK/STAT signaling. Conclusion: Human AEC JAK/STAT signaling activation regulates the early maturation of airway B-cell responses via local BAFF induction, particularly during viral infections.