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

Dehui Chang; Hao Zhang; Jing Ge; Qi Xing; Xinyi Guo; Xiaohu Wang; Chen Dong

doi:10.3389/fimmu.2023.1105145

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

Front Immunol. 2023 Mar 9:14:1105145. doi: 10.3389/fimmu.2023.1105145. eCollection 2023.

Authors

Dehui Chang¹, Hao Zhang¹, Jing Ge², Qi Xing¹, Xinyi Guo¹, Xiaohu Wang¹, Chen Dong^{1

2

3

4}

Affiliations

¹ Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.
² Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China.
³ Tsinghua University-Peking University Center for Life Sciences, Tsinghua University, Beijing, China.
⁴ Research Unit of Immune Regulation and Immune Diseases of Chinese Academy of Medical Sciences, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai, China.

Abstract

Background: 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 Rorc gene, in directing T helper 17 differentiation and related autoimmune disease. However, whether cis-acting elements regulate RORγt expression in ILC3s is unknown.

Results: 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⁺NKp46⁺ ILC3 population, though the overall numbers and frequencies of RORγt⁺ 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⁺NKp46⁺ ILC3 subset.

Conclusion: Our study thus identifies CNS9 as an essential cis-regulatory element controlling the lineage stability and plasticity of ILC3s through modulating expression levels of RORγt protein.

Keywords: ILC3s; CNS9; RORγt; cis-element; plasticity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / genetics
Immunity, Innate*
Lymphocytes*
Mice
Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism

Substances

Nuclear Receptor Subfamily 1, Group F, Member 3
Rorc protein, mouse

Grants and funding

This work was supported by grants from National Natural Science Foundation of China (31630022, 31821003 and 31991170 to C. Dong, 32070889 to X. Wang), Beijing Natural Science Foundation (5222011 to X. Wang) and Shanghai Science and Technology Commission (21JC1404200 to C. Dong.).