AbstractBackgroundAllergy to dogs affects around 10% of the population in developed countries. Immune therapy of allergic patients with dog allergen extracts has shown limited therapeutic benefit.MethodsWe established a mouse model of dog allergy by repeatedly administering dog dander and epithelium extracts via the intranasal route. We also assessed the efficacy of a recombinant multimeric protein containing Can f 1, f 2, f 4 and f 6 in preventing inflammatory responses to dog extracts.ResultsRepeated inhalation of dog extracts induced infiltration of the airways by T_H2 cells, eosinophils and goblet cells, reminiscent of the house dust mite (HDM) model of asthma. Dog extracts also induced robust airway hyperresponsiveness and promoted T_H17 cell responses, which was associated with a high neutrophilic infiltration of the airways. scRNA‐Seq analysis of T helper cells in the airways pinpointed a unique gene signature for T_H17 cells. Analysis of T‐cell receptors depicted a high frequency of clones that were shared between T_H17, T_H2 and suppressive Treg cells, indicative of a common differentiation trajectory for these subsets. Importantly, sublingual administration of multimeric Can f 1‐2‐4‐6 protein prior to sensitization reduced airway hyperresponsiveness and type 2‐mediated inflammation in this model.ConclusionDog allergen extracts induce robust T_H2 and T_H17 cell‐mediated responses in mice. Recombinant Can f 1‐2‐4‐6 can induce tolerance to complex dog allergen extracts.