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Transcriptional control of mature ILC3 function and plasticity: not just RORγt

Cellular & Molecular Immunology volume 19, pages 142–144 (2022)Cite this article

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Given their diverse phenotypes and cytokine-producing capacities, ILC subsets play different immune roles in tissues and collectively participate in immune defense. Since the first report on mature ILC plasticity [5, 6], plasticity has been considered a fundamental factor leading to the heterogeneity of ILCs [1]. In addition to cytokine induction, some lineage-defined transcription factors can control the fates, phenotypes and functions of ILC subsets [7, 8]. For example, in the absence of RORγt, CCR6−NKP46+ ILC3s can be converted into NK1.1+NKp46+ ILC1s with concomitant increased T-bet expression and interferon (IFN)-γ production resembling the ILC1 profile [6, 9]. Recently, multiple previously neglected transcription factors have been detected in ILC subsets simultaneously and participate in ILC regulation [10]. For example, RORα [11] was reported to maintain lineage-specific ILC3 characteristics. Therefore, understanding the role of combined transcription factors in the characteristic shift of tissue-resident mature ILCs will guide future research on ILC immunobiology and tissue immune microenvironment regulation.

The maintaining role of RORα in ILC3 identity is inconsistent with the prior concept that ILC3s are strictly dependent on RORγt. To decipher the contributions of RORγt and RORα to mature ILCs, Fiancette et al. [4] developed inducible deletion adult mouse models with RORγt- and RORα-depleted ILCs, namely, Id2iΔRORγt and Id2iΔRORγt/RORα mice. Then, these researchers performed single-cell RNA sequencing (scRNA-seq) of ILCs isolated from the lamella propria of the small intestine of these models and performed epigenetic, metabolic, and functional assays in vitro and in vivo. Overall, NCR+ and LTi-like ILC3s showed highly different sensitivity to RORγt and RORα deletion. Notably, deletion of either RORγt alone or together with RORα led to the transition of NCR+ ILC3s into ex-ILC3s or ILC1s with decreased ILC3-related genes, such as Rorc, Il22, Il23r, and Il1r, and consequently increased ILC1-defined transcription factor T-bet. Functionally, the secretion capacity of the ILC3-specific cytokines IL-22 and IL-17A was downregulated after IL-23 stimulation, whereas the secretion capacity of the ILC1-related cytokine IFN-γ and chemokine XCL1 was upregulated. Compared with RORγt depletion alone, the ex-ILC3 or ILC1 clusters from the RORγt- and RORα-depleted groups were more similar to the defined ILC1s at the cellular and transcriptomic levels, as shown by the enhanced expression of ILC1 markers (NKG2A, CD94, NKp46, and NK1.1). In contrast, unlike NCR+ ILC3s, loss of RORγt in LTi-like ILC3s had no significant impact on the master function to produce IL-22. Continuous deletion of RORγt and RORα caused reduced CCR6 and MHCII expression and IL-17A production. Nonetheless, LTi-like and CCR6−NKp46− ILC3s retained the ability to produce IL-22, which rectified the previous point that LTi-like ILC3s strictly depend on RORγt [1].

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Acknowledgements

This work was supported by grants from the Scientific and Technological Developing Plan of Jilin Province [grant number 20210402009GH].

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  1. Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China

    Xinping Lv, Shan Zhu, Jing Wu & Jingtao Chen

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Lv, X., Zhu, S., Wu, J. et al. Transcriptional control of mature ILC3 function and plasticity: not just RORγt. Cell Mol Immunol 19, 142–144 (2022). https://doi.org/10.1038/s41423-021-00816-3

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