Targeting the ICOS/ICOS‐L pathway in a mouse model of established allergic asthma disrupts T follicular helper cell responses and ameliorates disease. Issue 4 (12th November 2018)

• Record Type: Journal Article
• Authors: Uwadiae, Faith I.; Pyle, Chloe J.; Walker, Simone A.; Lloyd, Clare M.; Harker, James A.
• Is Part Of: Allergy. Volume 74:Issue 4(2019)
• Page Start: 650
• Page End: 662
• Publication Date: 2018-11-12
• Subjects: allergic airway disease -- germinal centres -- ICOS -- ICOS‐L -- T follicular helper cells; Allergy -- Periodicals; 616.97
• DOI: 10.1111/all.13602
• Languages: English
• ISSNs: 0105-4538

Abstract

Abstract: 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 (TFH ) are crucial in T‐dependent B‐cell responses and have been implicated in allergic airway disease (AAD). TFH, 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 TFH responses. However, the contribution of TFH 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 TFH 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: TFH were first observed in the lung‐draining lymph nodes and with further exposure were also found locally within the lungs. TFH accumulated with sustained allergen exposure, alongside germinal centre (GC) B cells. Blockade of ICOS signalling after AAD establishment successfully depleted TFH 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: TFH are crucial in the regulation of AAD and the ICOS/ICOS‐L pathway could represent a novel therapeutic target in allergic asthma. Abstract : Chronic allergen exposure drives T follicular helper cell (TFH) formation in the lung draining lymph node after 1 week and the lung tissue after 3 weeks TFH at both sites interact with germinal centre B cells and are critical for the production of allergen specific IgE Allergic disease is also hallmarked by cellular inflammation and airway hyperresponsiveness driven by IL‐13 Blocking ICOS and ICOS‐L interactions between TFH and B cells reduces allergen specific IgE production and also dampens other hallmark symptoms of allergic airway disease