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

Abstract

T follicular helper cells (T) 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 Tplay in AADs has remained elusive. Using a mouse model of chronic allergen induced AAD we now show that germinal centres (GCs) containing Tand 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, 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 Tand 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 Tdeficiency did not worsen allergic airways disease after 3 weeks of aero-allergen exposure, worsened lung function and enhanced T-based inflammation in the respiratory tract were seen following 5 weeks of exposure. Overall these data suggest that Tplay 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.