The Transcription Factor RORα Preserves ILC3 Lineage Identity and Function during Chronic Intestinal Infection

Innate lymphoid cells (ILCs) are critical for host defense and tissue repair but can also contribute to chronic inflammatory diseases. The transcription factor RORalpha is required for ILC2 development but is also highly expressed by other ILC subsets where its function remains poorly defined. We previously reported that Rora(sg/sg) bone marrow chimeric mice (C57BL/6J) were protected from Salmonella-induced intestinal fibrosis due to defective ILC3 responses. In this study, single-cell RNA analysis of ILCs isolated from inflamed tissues indicates that RORalpha perturbation led to a reduction in ILC3 lineages. Furthermore, residual Rora(sg/sg) ILC3s have decreased expression of key signature genes, including Rorc and activating cytokine receptors. Collectively, our data suggest that RORalpha plays a key role in preserving functional ILC3s by modulating their ability to integrate environmental cues to efficiently produce cytokines.