Reciprocal Transcription Factor Networks Govern Tissue-resident ILC3 Subset Function and Identity

Overview

Journal Nat Immunol

Date 2021 Sep 24

PMID 34556884

Citations 41

Authors

Remi Fiancette

Conor M Finlay

Claire Willis

Sarah L Bevington

Jake Soley

Sky T H Ng

Syed Murtuza Baker

Simon Andrews

Matthew R Hepworth

David R Withers

Affiliations

Soon will be listed here.

Abstract

Innate lymphoid cells (ILCs) are guardians of mucosal immunity, yet the transcriptional networks that support their function remain poorly understood. We used inducible combinatorial deletion of key transcription factors (TFs) required for ILC development (RORγt, RORα and T-bet) to determine their necessity in maintaining ILC3 identity and function. Both RORγt and RORα were required to preserve optimum effector functions; however, RORα was sufficient to support robust interleukin-22 production among the lymphoid tissue inducer (LTi)-like ILC3 subset, but not natural cytotoxicity receptor (NCR) ILC3s. Lymphoid tissue inducer-like ILC3s persisted with only selective loss of phenotype and effector functions even after the loss of both TFs. In contrast, continued RORγt expression was essential to restrain transcriptional networks associated with type 1 immunity within NCR ILC3s, which coexpress T-bet. Full differentiation to an ILC1-like population required the additional loss of RORα. Together, these data demonstrate how TF networks integrate within mature ILCs after development to sustain effector functions, imprint phenotype and restrict alternative differentiation programs.

Citing Articles

RORγt-expressing dendritic cells are functionally versatile and evolutionarily conserved antigen-presenting cells.

Narasimhan H, Richter M, Shakiba R, Papaioannou N, Stehle C, Ravi Rengarajan K Proc Natl Acad Sci U S A. 2025; 122(9):e2417308122.

PMID: 39993193 PMC: 11892598. DOI: 10.1073/pnas.2417308122.

Group 3 Innate Lymphoid Cells: A Potential Therapeutic Target for Steroid Resistant Asthma.

Berkinbayeva M, Gu W, Chen Z, Gao P Clin Rev Allergy Immunol. 2025; 68(1):1.

PMID: 39751959 PMC: 11698894. DOI: 10.1007/s12016-024-09012-3.

CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner.

Lo J, Schroeder J, Roberts L, Mohamed R, Cozzetto D, Beattie G Nat Commun. 2024; 15(1):9520.

PMID: 39496592 PMC: 11535242. DOI: 10.1038/s41467-024-51719-6.

Bridging Chronic Inflammation and Digestive Cancer: The Critical Role of Innate Lymphoid Cells in Tumor Microenvironments.

Shen G, Wang Q, Li Z, Xie J, Han X, Wei Z Int J Biol Sci. 2024; 20(12):4799-4818.

PMID: 39309440 PMC: 11414386. DOI: 10.7150/ijbs.96338.

Prdm16-dependent antigen-presenting cells induce tolerance to intestinal antigens.

Fu L, Upadhyay R, Pokrovskii M, Chen F, Romero-Meza G, Griesemer A bioRxiv. 2024; .

PMID: 39091750 PMC: 11291166. DOI: 10.1101/2024.07.23.604803.

References

Vonarbourg C, Mortha A, Bui V, Hernandez P, Kiss E, Hoyler T . Regulated expression of nuclear receptor RORγt confers distinct functional fates to NK cell receptor-expressing RORγt(+) innate lymphocytes. Immunity. 2010; 33(5):736-51. PMC: 3042726. DOI: 10.1016/j.immuni.2010.10.017. View

Walker J, Barlow J, McKenzie A . Innate lymphoid cells--how did we miss them?. Nat Rev Immunol. 2013; 13(2):75-87. DOI: 10.1038/nri3349. View

Brewitz A, Eickhoff S, Dahling S, Quast T, Bedoui S, Kroczek R . CD8 T Cells Orchestrate pDC-XCR1 Dendritic Cell Spatial and Functional Cooperativity to Optimize Priming. Immunity. 2017; 46(2):205-219. PMC: 5362251. DOI: 10.1016/j.immuni.2017.01.003. View

Aibar S, Gonzalez-Blas C, Moerman T, Huynh-Thu V, Imrichova H, Hulselmans G . SCENIC: single-cell regulatory network inference and clustering. Nat Methods. 2017; 14(11):1083-1086. PMC: 5937676. DOI: 10.1038/nmeth.4463. View

Buenrostro J, Wu B, Chang H, Greenleaf W . ATAC-seq: A Method for Assaying Chromatin Accessibility Genome-Wide. Curr Protoc Mol Biol. 2015; 109:21.29.1-21.29.9. PMC: 4374986. DOI: 10.1002/0471142727.mb2129s109. View

Cella M, Gamini R, Secca C, Collins P, Zhao S, Peng V . Subsets of ILC3-ILC1-like cells generate a diversity spectrum of innate lymphoid cells in human mucosal tissues. Nat Immunol. 2019; 20(8):980-991. PMC: 6685551. DOI: 10.1038/s41590-019-0425-y. View

Robinson M, McCarthy D, Smyth G . edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2009; 26(1):139-40. PMC: 2796818. DOI: 10.1093/bioinformatics/btp616. View

Scott C, TJonck W, Martens L, Todorov H, Sichien D, Soen B . The Transcription Factor ZEB2 Is Required to Maintain the Tissue-Specific Identities of Macrophages. Immunity. 2018; 49(2):312-325.e5. PMC: 6104815. DOI: 10.1016/j.immuni.2018.07.004. View

Sojka D, Plougastel-Douglas B, Yang L, Pak-Wittel M, Artyomov M, Ivanova Y . Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells. Elife. 2014; 3:e01659. PMC: 3975579. DOI: 10.7554/eLife.01659. View

10.

Klose C, Kiss E, Schwierzeck V, Ebert K, Hoyler T, dHargues Y . A T-bet gradient controls the fate and function of CCR6-RORγt+ innate lymphoid cells. Nature. 2013; 494(7436):261-5. DOI: 10.1038/nature11813. View

11.

Bai L, Vienne M, Tang L, Kerdiles Y, Etiennot M, Escaliere B . Liver type 1 innate lymphoid cells develop locally via an interferon-γ-dependent loop. Science. 2021; 371(6536). DOI: 10.1126/science.aba4177. View

12.

Sanos S, Bui V, Mortha A, Oberle K, Heners C, Johner C . RORgammat and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nat Immunol. 2008; 10(1):83-91. PMC: 4217274. DOI: 10.1038/ni.1684. View

13.

Peng H, Jiang X, Chen Y, Sojka D, Wei H, Gao X . Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J Clin Invest. 2013; 123(4):1444-56. PMC: 3613925. DOI: 10.1172/JCI66381. View

14.

Sawa S, Cherrier M, Lochner M, Satoh-Takayama N, Fehling H, Langa F . Lineage relationship analysis of RORgammat+ innate lymphoid cells. Science. 2010; 330(6004):665-9. DOI: 10.1126/science.1194597. View

15.

Street K, Risso D, Fletcher R, Das D, Ngai J, Yosef N . Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genomics. 2018; 19(1):477. PMC: 6007078. DOI: 10.1186/s12864-018-4772-0. View

16.

Shih H, Sciume G, Mikami Y, Guo L, Sun H, Brooks S . Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality. Cell. 2016; 165(5):1120-1133. PMC: 4874839. DOI: 10.1016/j.cell.2016.04.029. View

17.

Choi G, Yim Y, Wong H, Kim S, Kim H, Kim S . The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science. 2016; 351(6276):933-9. PMC: 4782964. DOI: 10.1126/science.aad0314. View

18.

Halim T, MacLaren A, Romanish M, Gold M, McNagny K, Takei F . Retinoic-acid-receptor-related orphan nuclear receptor alpha is required for natural helper cell development and allergic inflammation. Immunity. 2012; 37(3):463-74. DOI: 10.1016/j.immuni.2012.06.012. View

19.

Hirota K, Duarte J, Veldhoen M, Hornsby E, Li Y, Cua D . Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol. 2011; 12(3):255-63. PMC: 3040235. DOI: 10.1038/ni.1993. View

20.

Oliphant C, Hwang Y, Walker J, Salimi M, Wong S, Brewer J . MHCII-mediated dialog between group 2 innate lymphoid cells and CD4(+) T cells potentiates type 2 immunity and promotes parasitic helminth expulsion. Immunity. 2014; 41(2):283-95. PMC: 4148706. DOI: 10.1016/j.immuni.2014.06.016. View