Diverse IL-9-secreting T helper cells direct responses in the allergic lung

IL-9 promotes airway hyperresponsiveness, eosinophilia, mast cell expansion, and antibody-mediated inflammation through interactions with mast cells, eosinophils, B cells, and airway and lung macrophages in models of allergic airway disease. IL-9 has increasingly been linked to asthma severity in patients. Early studies primarily focused on the differentiation of "classical" Th9 cells, which express IL-9 but not other type II cytokines. Recent research has identified additional populations of IL-9-secreting CD4⁺ T cells, including Th2-allergic (Th2A) cells and resident memory Th9 (Th9rm) cells. Despite IL-9 induction in classical Th9 effector cells being transient, Th2A and memory populations generate a recall IL-9 response upon repeated allergen exposure. Additionally, cytokine-driven bystander activation may prolong IL-9 production in various CD4⁺ T cell subsets. This review evaluates the transcriptional, metabolic, and cytokine-mediated signals that regulate the effector function of IL-9-secreting CD4⁺ T cell subsets in models of acute, chronic, and intermittent allergic airway disease. Given the heterogeneity of asthma phenotypes, identifying endotypes characterized by high levels of Th9 cells or IL-9 may improve therapeutic precision in asthma treatment.