IL-9-secreting tissue-resident memory CD4+ T cells contribute to allergic airway recall responses

Abstract

Abstract Asthma is a chronic intermittent inflammatory lung disease for which there is no cure. Allergen-specific CD4 T helper (Th) cells that secrete cytokines including IL-4, IL-13, and IL-9 mediate asthma pathogenesis. In a six week chronic model of allergic airway disease, we were able to detect a robust IL-9+CD4+ T cell population in the lungs. Interestingly, the in vivo derived IL-9+CD4+ T cells had a multi-cytokine profile including the production of IL-5, IL-13, and IL-10. IL-9-reporter-positive cells demonstrated high gene expression levels of innate cytokine receptors Il1rl1, Il17rb, and Crlf2 and the transcription factor Gata3. IL-9+CD4+ T cells were found to be tissue-resident through intravenous labeling and had CD4+ tissue-resident memory (Trm) cell markers CD69 and CD11a. To determine the Trm phenotype of lung resident IL-9+ T cells, we developed a memory model using a five week period of rest after six weeks of chronic challenge, before a recall allergen challenge. In the memory model, IL-9+ T cells maintained tissue residency and demonstrated increased cell frequency and IL-9 production, characteristic of a secondary response. Antibody blockade of IL-9 immediately prior to the recall challenge significantly reduced overall allergic lung inflammation, suggesting that IL-9 plays an obligate role in the allergic memory response following pulmonary allergen challenge. These observations further suggest that IL-9 from Trm cell populations plays a novel role in allergen recall responses and is a potential therapeutic target for patients suffering from chronic intermittent asthma.