Targeting the ICOS/ICOS‐L pathway in a mouse model of established allergic asthma disrupts T follicular helper cell responses and ameliorates disease

BACKGROUND: Allergic asthma is characterized by chronic inflammation and remodelling of the airways, associated with dysregulated type 2 immune responses and allergen‐specific IgE. T follicular helper cells (T(FH)) are crucial in T‐dependent B‐cell responses and have been implicated in allergic airway disease (AAD). T(FH), unlike other CD4(+) T cells, are uniquely reliant on continuous ICOS signalling to maintain their phenotype after T‐cell priming; therefore, disrupting this signal can impair T(FH) responses. However, the contribution of T(FH) to disease during chronic aero‐allergen exposure and the therapeutic potential of targeting these cells have not been evaluated. METHODS: To establish AAD, female BALB/c mice were repeatedly exposed to house dust mite or Alternaria alternata three times a week for up to 5 weeks. To examine the impact of T(FH) on AAD, mice were allergen exposed for 5 weeks and co‐administered anti‐ICOS Ligand‐targeted antibodies, three times a week for the last 2 weeks. RESULTS: T(FH) were first observed in the lung‐draining lymph nodes and with further exposure were also found locally within the lungs. T(FH) accumulated with sustained allergen exposure, alongside germinal centre (GC) B cells. Blockade of ICOS signalling after AAD establishment successfully depleted T(FH) but did not affect the differentiation of other CD4(+) T‐cell subsets. This reduced GC responses, allergen‐specific IgE, inflammation, pulmonary IL‐13 and airway hyper‐responsiveness. CONCLUSIONS: T(FH) are crucial in the regulation of AAD and the ICOS/ICOS‐L pathway could represent a novel therapeutic target in allergic asthma.