T follicular helper cells (TFH) are critical regulators of antibody production and have been implicated in several diseases of abnormal antibody generation. However, the role that TFH play in the pathogenesis of allergic asthma is little understood. Therefore the aim of this thesis was to further examine their contribution using clinical relevant mouse models of chronic allergic airway disease (AAD).
During chronic AAD TFH were first found in the mediastinal lymph node (mLN), and with further allergen exposure in the spleen and the lung tissue. TFH induced during chronic AAD were bona fide, tissue resident TFH which expressed CXCR5, PD1, ICOS, Bcl-6 and produced IL-4 and IL-21. Interestingly, lung TFH were more skewed towards a TFH17 phenotype and also expressed Rorgt, CCR6 and produced IL-17A.
TFH were accompanied by germinal centre (GC) B cells, memory B cells and plasma cells, and the generation of these cellular populations and allergic specific antibodies was completely dependent on TFH. Large tertiary lymphoid structures (TLS), complete with GCs were also found in lungs and their formation was partly dependent on cellular recruitment to the lungs, IL-17A driven B cell aggregation and TFH. The lungs were an active site of class switching to IgA, in addition to IgE and IgG1, suggesting the lungs to be a local site of both protective and pathogenic antibody production.
TFH could be therapeutically targeted during established chronic AAD by administration of ICOS-L blocking antibodies. This reduction in TFH populations was accompanied by decreased GC B cells, allergen specific IgE, and improved hallmark AAD symptoms. Interestingly, TFH were also found to be regulators of chronic AAD, and their absence at the inception of chronic AAD led to enhanced type 2 biased inflammation and worsened airway function. Collectively, these findings show TFH to be important regulators and drivers of chronic AAD.