Appearing where it matters: Ectopic Germinal Centers in the Respiratory Tract after influenza infection

• Upper and lower airway eGCs shape anti-influenza immunity • eGC have unique developmental and maintenance features • Targeting eGC offers new opportunities for durable mucosal influenza vaccines Influenza A virus infects the host through the respiratory mucosa, yet most vaccines are designed to elicit immune responses in secondary lymphoid organs that are anatomically distant from the site of infection. While efficient at generating systemic immunity, these strategies often provide limited protection at mucosal surfaces. Recent studies have shown that infection-driven inflammation can induce the formation of tertiary lymphoid structures (TLS) throughout the respiratory tract, both in lungs but also in nasal tissue. Within these structures, ectopic germinal centers (eGCs) arise directly at sites of viral replication, supporting local B-cell activation, somatic hypermutation, class-switch recombination, and the generation of memory and antibody-secreting cells. Although eGCs share key features with conventional germinal centers, they develop under distinct inflammatory and stromal conditions that may influence B-cell selection as well as immune output which should be taken into consideration for future mucosal vaccine strategies. In this review, we summarize current understanding of respiratory eGC formation and function during influenza infection in mice and humans. We compare ectopic and conventional germinal center reactions, but also the eGC in lungs vs nasal tissues, discuss the local cues that drive TLS formation and how eGCs contribute to B cell selection and differentiation. Finally, we discuss how these insights may inform future influenza vaccine strategies aimed at engaging respiratory TLS to enhance durable mucosal immunity.