ICOS-driven Cholesterol and Cortisol Biosynthesis Shape IL-10 Production in ILC2s to Regulate Airway Hyperreactivity

Group 2 innate lymphoid cells (ILC2) induce type 2 inflammation in the lungs in response to allergens. Here, we investigated the regulatory mechanism of IL-10 production by ILC2s on the development of airway hyperreactivity (AHR), with a particular focus on the role of ICOS. Our findings demonstrate that inhibition of ICOS in pulmonary ILC2s significantly promotes IL-10 production. Lack of ICOS reprograms ILC2 steroid metabolism, resulting in increased cholesterol and cortisol biosynthesis and Glucocorticoid receptor (GR) activation. Consequently, this reprogramming regulates MAF and NFIL3 activation, thereby promoting IL-10 production. We notably found that in vivo GR inhibition or ILC2-specific GR deficiency exacerbated the development of AHR in multiple mouse models. Finally, we extended our findings to a human setting and demonstrated concordant results between murine models and human ILC2s. Taken together, our results therefore indicate that ICOS negatively regulates IL-10 production in ILC2s by controlling cholesterol and cortisol biosynthesis. Overall design: mRNA profiles of mouse lung ILC2s from WT and ICOS KO mice were generated by deep sequencing, in duplicates, using a NextSeq 500.