Autocrine IL-9 production by ILC2s promotes their expansion and effector responses, including IL-5-driven eosinophilia, in response to airway allergens. In contrast, Th2 cell-intrinsic IL-9R signaling is dispensable for type 2 lung inflammation. Lung monocytes, macrophages, and DCs do not respond to IL-9 in asthma models due to the absence of IL-9R expression.
ABSTRACT
Interleukin-9 (IL-9) has primarily been associated with type 2 immunity in health and disease. While its impact on innate lymphoid cells (ILC2s) is well known, the cellular targets and mechanisms underlying type 2 immunity remain incompletely understood. In this study, we report the generation of a mouse-specific anti-IL-9 receptor (IL-9R) antibody, enabling us to accurately map IL-9R protein expression across various immune cell types. In naïve mice, IL-9R was detectable in ILC2s, marginal zone B cells, and B1b cells. In allergic lung inflammation, a subset of CD4+ T cells faintly upregulated IL-9R, whereas DCs, macrophages, eosinophils, and neutrophils remained IL-9R-negative. Functionally, IL-9R was found to significantly contribute to ILC2 expansion, their effector cytokine production, and eosinophilia in the papain asthma model. However, in the context of acute and chronic HDM exposure, IL-9R was dispensable for both allergic lung inflammation and CD4-dependent memory-type 2 responses. Using mixed bone marrow chimeras in which IL-9R is selectively absent in T cells, we confirmed that IL-9R signaling in T cells does not critically impact chronic Th2 and Th17 responses. Lastly, using mice selectively lacking ILC2s, we demonstrate that this population is the culprit of pathological type 2 immunity in the lung in both papain- and acute HDM-induced asthma models. Together, our results establish that IL-9 is a critical regulator of ILC2-dependent type 2 immunity, while its effects on T cell-dependent responses are minimal. These findings provide a foundation for future studies exploring the therapeutic modulation of IL-9 signaling in allergy and other inflammatory diseases.