TH9-derived IL-9 promotes CCR2-dependent mast cell accumulation in the allergic lung

Abstract

Abstract Allergic asthma is a chronic lung disease characterized by airway hyperresponsiveness and cellular infiltration that is exacerbated by IgE-dependent mast cell activation. Our work in mouse models of allergic airway inflammation identified interleukin-9 (IL-9)-producing T helper 9 (TH9) cells as important effector cells in promoting mast cell accumulation in the lungs. However, the precise mechanism of IL-9-mediated mast cell expansion remains unclear. Here, we demonstrate that intranasal recombinant IL-9 expands, while blockade of IL-9 reduces, mast cell progenitor numbers in the lungs and the bone marrow. These findings suggests that there are systemic effects of local IL-9 production in the allergic lung. Using adoptive transfer models and newly generated mice with an inactivation of the IL-9 gene restricted to T cells generated by CD4-Cre/loxP-mediated targeting of the IL-9 gene, we show that TH9 cells promote mast cell progenitor and mature mast cell recruitment from the bone marrow to the lungs in a chemokine receptor 2-dependent manner. Our research further demonstrates that T cell-derived IL-9 is critical for mast cell-mediated airway hyperresponsiveness. Together, these findings define a contribution of T cell-derived IL-9 in promoting mast cell expansion and function in allergic airway inflammation. Therefore, IL-9 may be a promising therapeutic target for targeting mast cell-specific pathologies. Supported by grants from NIH (R01 AI129241, T32 AI060519)