IL-10 production by ILC2s requires Blimp-1 and cMaf, modulates cellular metabolism, and ameliorates airway hyperreactivity.

Abstract

Group 2 innate lymphoid cells (ILC2s) are the dominant innate lymphoid cell population in the lungs at steady state, and their release of type 2 cytokines is a central driver in responding eosinophil infiltration and increased airway hyperreactivity. Our laboratory has identified a unique subset of ILC2s in the lungs that actively produce IL-10 (ILC2₁₀s). Our aim was to characterize the effector functions of ILC2₁₀s in the development and pathology of allergic asthma. IL-4-stimulated ILC2₁₀s were isolated to evaluate cytokine secretion, transcription factor signaling, metabolic dependence, and effector functions in vitro. ILC2₁₀s were also adoptively transferred into Rag2^-/-γc^-/- mice, which were then challenged with IL-33 and assessed for airway hyperreactivity and lung inflammation. We have determined that the transcription factors cMaf and Blimp-1 regulate IL-10 expression in ILC2₁₀s. Strikingly, our results demonstrate that ILC2₁₀s can utilize both autocrine and paracrine signaling to suppress proinflammatory ILC2 effector functions in vitro. Further, this subset dampens airway hyperreactivity and significantly reduces lung inflammation in vivo. Interestingly, ILC2₁₀s demonstrated a metabolic dependency on the glycolytic pathway for IL-10 production, shifting from the fatty acid oxidation pathway conventionally utilized for proinflammatory effector functions. These findings provide an important and previously unrecognized role of ILC2₁₀s in diseases associated with ILC2s such as allergic lung inflammation and asthma. They also provide new insights into the metabolism dependency of proinflammatory and anti-inflammatory ILC2 phenotypes.