T follicular helper cells drive functionally distinct lymphoid and lung resident germinal centres and limit allergic...

T follicular helper cells (T_FH) play a central role in orchestrating antibody mediated immunity. Despite the importance of antibody responses, especially allergen-specific IgE, in allergic airway diseases (AAD) such as asthma, the precise role T_FH play in AADs has remained elusive. Using a mouse model of chronic allergen induced AAD we now show that germinal centres (GCs) containing T_FH and GC B cells accumulate in both the lung draining lymph nodes (dLNs) and the lungs themselves after allergen exposure. The formation of these GCs is dependent on T_FH, as is generation of allergen specific IgA, IgG and IgE, with IgG1 and IgE-switched B cells being predominantly found in the dLNs while IgA switched B cells were only found in the lungs. Fitting with this, allergen-induced lung resident T_FH and B cells are functionally and transcriptionally distinct from their lymphoid counterparts, with lung GCs providing a unique site of IgA-switch, a process that is partially IL-17A dependent. Finally while T_FH deficiency did not worsen allergic airways disease after 3 weeks of aero-allergen exposure, worsened lung function and enhanced T_H2-based inflammation in the respiratory tract were seen following 5 weeks of exposure. Overall these data suggest that T_FH play a pivotal role in shaping immune responses both in the dLNs and the respiratory tract, and while they can promote key type-2 inflammatory pathways such as IgE production, they can also act to limit prolonged type-2 inflammation.