Allergic airway recall responses require IL-9 from resident memory CD4 ⁺ T cells

Abstract

Asthma is a chronic inflammatory lung disease with intermittent flares predominately mediated through memory T cells. Yet, the identity of long-term memory cells that mediate allergic recall responses is not well defined. In this report, using a mouse model of chronic allergen exposure followed by an allergen-free rest period, we characterized a subpopulation of CD4 + T cells that secreted IL-9 as an obligate effector cytokine. IL-9–secreting cells had a resident memory T cell phenotype, and blocking IL-9 during a recall challenge or deleting IL-9 from T cells significantly diminished airway inflammation and airway hyperreactivity. T cells secreted IL-9 in an allergen recall–specific manner, and secretion was amplified by IL-33. Using scRNA-seq and scATAC-seq, we defined the cellular identity of a distinct population of T cells with a proallergic cytokine pattern. Thus, in a recall model of allergic airway inflammation, IL-9 secretion from a multicytokine-producing CD4 + T cell population was required for an allergen recall response.

Mouse pulmonary interstitial macrophages mediate the pro-tumorigenic effects of IL-9

“…1o ). To confirm the importance of IL-9 from T cells, mice with T cell-specific ablation of Il9 were injected with B16 tumor cells 26 . Compared to control mice, Il9 fl/fl CD4-Cre + mice showed less tumor growth and decreased IM populations (Fig.…”

“…INFER mice were provided by Dr. Paula Licona-Limón and Dr. Richard A. Flavell 54 . Il9 fl/fl crossed to CD4-Cre transgenics were recently described 26 . Both female and male mice were used between the age of 8 weeks to 16 weeks.…”

Functional Recognition Theory and Type 2 Immunity: Insights and Uncertainties

“…Notably, IL-9 is predominantly expressed in highly differentiated CD4 1 Th2 cells, indicating that chronic stimulation is necessary for induction of the Th9 program (110). In murine models of allergic lung inflammation, short-term allergen exposure protocols do not seem to induce a significant Th9 cell subset, whereas chronic allergen treatments yield a distinct subset of Th9 cells (109,116). After chronic allergen exposure, IL-9 is predominantly derived from a population of tissue-resident memory CD4 1 T cells that exhibit a distinct chromatin and transcriptional signature from CD4 1 Th2 cells (109).…”

“…In murine models of allergic lung inflammation, short-term allergen exposure protocols do not seem to induce a significant Th9 cell subset, whereas chronic allergen treatments yield a distinct subset of Th9 cells (109,116). After chronic allergen exposure, IL-9 is predominantly derived from a population of tissue-resident memory CD4 1 T cells that exhibit a distinct chromatin and transcriptional signature from CD4 1 Th2 cells (109). Tissue-resident memory Th9 cells produced IL-9 in an allergen-specific manner, which is enhanced by IL-33 (109).…”

“…After chronic allergen exposure, IL-9 is predominantly derived from a population of tissue-resident memory CD4 1 T cells that exhibit a distinct chromatin and transcriptional signature from CD4 1 Th2 cells (109). Tissue-resident memory Th9 cells produced IL-9 in an allergen-specific manner, which is enhanced by IL-33 (109). Beyond CD4 1 Th2 and Th9 cells, the induction of IgE significantly enhances the ability of mast cells to respond in an Ag-specific manner (117).…”