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

Background: 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 (ILC2(10)s). Objective: Our aim was to characterize the effector functions of ILC2(10)s in the development and pathology of allergic asthma. Methods: IL-4-stimulated ILC2(10)s were isolated to evaluate cytokine secretion, transcription factor signaling, metabolic dependence, and effector functions in vitro. ILC2(10)s were also adoptively transferred into Rag2(-/-) gamma c(-/-) mice, which were then challenged with IL-33 and assessed for airway hyperreactivity and lung inflammation. Results: We have determined that the transcription factors cMaf and Blimp-1 regulate IL-10 expression in ILC2(10)s. Strikingly, our results demonstrate that ILC2(10)s 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, ILC2(10)s 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. Conclusion: These findings provide an important and previously unrecognized role of ILC2(10)s 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.

Automated summary

The study identified a unique subset of ILC2s, known as ILC2(10)s, which actively produce IL-10 to suppress proinflammatory ILC2 functions through autocrine and paracrine signaling, resulting in reduced lung inflammation and airway hyperresponsiveness in vivo. Furthermore, the research highlights the metabolic dependency of ILC2(10)s on the glycolytic pathway for IL-10 production, contrasting with the conventional fatty acid oxidation pathway used for proinflammatory effector functions.