AUTHOR=Chang Dehui , Zhang Hao , Ge Jing , Xing Qi , Guo Xinyi , Wang Xiaohu , Dong Chen 

TITLE=A cis-element at the Rorc locus regulates the development of type 3 innate lymphoid cells

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1105145

DOI=10.3389/fimmu.2023.1105145

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>As an important early source of IL-17A and IL-22 in immune responses, type 3 innate lymphoid cells (ILC3s) are critically regulated by the transcription factor retinoic-acid-receptor-related orphan receptor gamma t (RORγt). Previously, we have identified a crucial role of the conserved non-coding sequence 9 (CNS9), located at +5,802 to +7,963 bp of the <italic>Rorc</italic> gene, in directing T helper 17 differentiation and related autoimmune disease. However, whether <italic>cis</italic>-acting elements regulate RORγt expression in ILC3s is unknown.</p></sec><sec><title>Results</title><p>Here we show that CNS9 deficiency in mice not only decreases ILC3 signature gene expression and increases ILC1-gene expression features in total ILC3s, but also leads to generation of a distinct CD4<sup>+</sup>NKp46<sup>+</sup> ILC3 population, though the overall numbers and frequencies of RORγt<sup>+</sup> ILC3s are not affected. Mechanistically, CNS9 deficiency selectively decreases RORγt expression in ILC3s, which thus alters ILC3 gene expression features and promotes cell-intrinsic generation of CD4<sup>+</sup>NKp46<sup>+</sup> ILC3 subset.</p></sec><sec><title>Conclusion</title><p>Our study thus identifies CNS9 as an essential <italic>cis</italic>-regulatory element controlling the lineage stability and plasticity of ILC3s through modulating expression levels of RORγt protein.</p></sec>