{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T21:10:44Z","timestamp":1792444244145,"version":"4.5.0"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,7]],"date-time":"2023-03-07T00:00:00Z","timestamp":1678147200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81970500, 82172645, 82002082"],"award-info":[{"award-number":["81970500, 82172645, 82002082"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Innate lymphoid cells (ILCs) are key components of the immune system, yet the similarity and distinction of the properties across tissues under homeostasis, inflammation and tumor process remain elusive.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here we performed integrative inference of ILCs to reveal their transcriptional profiles and heterogeneity from single-cell genomics. We collected a large number of ILCs from human six different tissues which can represent unique immune niches (circulation, lymphoid tissue, normal and inflamed mucosa, tumor microenvironment), to systematically address the transcriptional imprinting.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>ILCs are profoundly imprinted by their organ of residence, and tissue-specific distinctions are apparent under pathological conditions. In the hepatocellular carcinoma microenvironment, we identified intermediate c-kit<jats:sup>+<\/jats:sup> ILC2 population, and lin<jats:sup>-<\/jats:sup>CD127<jats:sup>-<\/jats:sup> NK-like cells that expressed markers of cytotoxicity including <jats:italic>CCL5<\/jats:italic> and <jats:italic>IFNG<\/jats:italic>. Additionally, CD127<jats:sup>+<\/jats:sup>CD94<jats:sup>+<\/jats:sup> ILC1s were preferentially enriched in inflamed ileum from patients with Crohn\u2019s disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These analyses depicted a comprehensive characterization of ILC anatomical distribution and subset heterogeneity, and provided a base line for future temporal or spatial studies focused on tissue-specific ILC-mediated immunity.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1127413","type":"journal-article","created":{"date-parts":[[2023,3,7]],"date-time":"2023-03-07T06:16:46Z","timestamp":1678169806000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Tissue specific imprinting on innate lymphoid cells during homeostasis and disease process revealed by integrative inference of single-cell transcriptomics"],"prefix":"10.3389","volume":"14","author":[{"given":"Peng","family":"Song","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonghuan","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shichao","family":"Ai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiongyuan","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxian","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofei","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1016\/j.immuni.2019.01.012","article-title":"Spatial and temporal mapping of human innate lymphoid cells reveals elements of tissue specificity","volume":"50","author":"Yudanin","year":"2019","journal-title":"Immunity"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01127-z","article-title":"Innate lymphoid cells and cancer","volume":"23","author":"Jacquelot","year":"2022","journal-title":"Nat Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20191520","article-title":"Ilc2s are the predominant source of intestinal ilc-derived il-10","volume":"217","author":"Bando","year":"2020","journal-title":"J Exp Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41385-020-00353-8","article-title":"Campylobacter infection promotes ifn\u03b3-dependent intestinal pathology Via Ilc3 to Ilc1 conversion","volume":"14","author":"Muraoka","year":"2021","journal-title":"Mucosal Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3800","article-title":"Tumor immunoevasion by the conversion of effector nk cells into type 1 innate lymphoid cells","volume":"18","author":"Gao","year":"2017","journal-title":"Nat Immunol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.immuni.2011.11.016","article-title":"The transcription factors T-bet and eomes control key checkpoints of natural killer cell maturation","volume":"36","author":"Gordon","year":"2012","journal-title":"Immunity"},{"key":"B7","doi-asserted-by":"publisher","first-page":"5446","DOI":"10.1038\/s41467-021-25758-2","article-title":"Sequential actions of eomes and T-bet promote stepwise maturation of natural killer cells","volume":"12","author":"Zhang","year":"2021","journal-title":"Nat Commun"},{"key":"B8","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1038\/s41577-022-00704-5","article-title":"Heterogeneity of type 2 innate lymphoid cells","volume":"22","author":"Spits","year":"2022","journal-title":"Nat Rev Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2013.3","article-title":"Innate lymphoid cells: From border protection to the initiation of inflammatory diseases","volume":"91","author":"Sanos","year":"2013","journal-title":"Immunol Cell Biol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/s41419-019-1540-2","article-title":"Ilc3 function as a double-edged sword in inflammatory bowel diseases","volume":"10","author":"Zeng","year":"2019","journal-title":"Cell Death Dis"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-020-00445-x","article-title":"Tissue-specific transcriptional imprinting and heterogeneity in human innate lymphoid cells revealed by full-length single-cell rna-sequencing","volume":"31","author":"Mazzurana","year":"2021","journal-title":"Cell Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2021-325288","article-title":"The tumour microenvironment shapes innate lymphoid cells in patients with hepatocellular carcinoma","volume":"71","author":"Heinrich","year":"2022","journal-title":"Gut"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1080\/2162402x.2022.2057396","article-title":"Innate lymphoid cells: Nk and cytotoxic Ilc3 subsets infiltrate metastatic breast cancer lymph nodes","volume":"11","author":"Rethacker","year":"2022","journal-title":"Oncoimmunology"},{"key":"B14","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1016\/j.cell.2019.08.006","article-title":"Cell type purification by single-cell transcriptome-trained sorting","volume":"179","author":"Baron","year":"2019","journal-title":"Cell"},{"key":"B15","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.cels.2018.11.005","article-title":"Scrublet: Computational identification of cell doublets in single-cell transcriptomic data","volume":"8","author":"Wolock","year":"2019","journal-title":"Cell Syst"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bby011","article-title":"Evaluation of tools for highly variable gene discovery from single-cell rna-seq data","volume":"20","author":"Yip","year":"2019","journal-title":"Brief Bioinform"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0619-0","article-title":"Fast, sensitive and accurate integration of single-cell data with harmony","volume":"16","author":"Korsunsky","year":"2019","journal-title":"Nat Methods"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1873","DOI":"10.1016\/j.cell.2019.05.006","article-title":"Single-cell multi-omic integration compares and contrasts features of brain cell identity","volume":"177","author":"Welch","year":"2019","journal-title":"Cell"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1126\/science.abe6474","article-title":"Pan-cancer single-cell landscape of tumor-infiltrating T cells","volume":"374","author":"Zheng","year":"2021","journal-title":"Science"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.xinn.2021.100141","article-title":"Clusterprofiler 4.0: A universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation (Camb)"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.1016\/j.ccell.2022.10.008","article-title":"High-resolution single-cell atlas reveals diversity and plasticity of tissue-resident neutrophils in non-small cell lung cancer","volume":"40","author":"Salcher","year":"2022","journal-title":"Cancer Cell"},{"key":"B22","doi-asserted-by":"publisher","first-page":"5692","DOI":"10.1038\/s41467-021-25960-2","article-title":"Confronting false discoveries in single-cell differential expression","volume":"12","author":"Squair","year":"2021","journal-title":"Nat Commun"},{"key":"B23","doi-asserted-by":"publisher","first-page":"5841","DOI":"10.1038\/s41467-021-26187-x","article-title":"Cd127+ Cd94+ innate lymphoid cells expressing granulysin and perforin are expanded in patients with crohn's disease","volume":"12","author":"Krabbendam","year":"2021","journal-title":"Nat Commun"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2021.100353","article-title":"Single-cell transcriptomic landscape reveals tumor specific innate lymphoid cells associated with colorectal cancer progression","volume":"2","author":"Qi","year":"2021","journal-title":"Cell Rep Med"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1834524100","article-title":"Transcription factor jund, deprived of menin, switches from growth suppressor to growth promoter","volume":"100","author":"Agarwal","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B26","doi-asserted-by":"publisher","first-page":"e54133","DOI":"10.15252\/embr.202154133","article-title":"Engagement of trail triggers degranulation and ifn\u03b3 production in human natural killer cells","volume":"23","author":"H\u00f6fle","year":"2022","journal-title":"EMBO Rep"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32444","article-title":"Single-cell profiling of human Cd127(+) innate lymphoid cells reveals diverse immune phenotypes in hepatocellular carcinoma","volume":"76","author":"He","year":"2022","journal-title":"Hepatology"},{"key":"B28","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1016\/j.immuni.2020.12.013","article-title":"Induction of il-10-Producing type 2 innate lymphoid cells by allergen immunotherapy is associated with clinical response","volume":"54","author":"Golebski","year":"2021","journal-title":"Immunity"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1800852","article-title":"Cutting edge: Core binding factor B is required for group 2 innate lymphoid cell activation","volume":"202","author":"Shen","year":"2019","journal-title":"J Immunol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"3225","DOI":"10.3390\/cancers13133225","article-title":"Immune circuits to shape natural killer cells in cancer","volume":"13","author":"Mattiola","year":"2021","journal-title":"Cancers"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.2013.782287","article-title":"Targeting tgf-B signaling in cancer","volume":"17","author":"Katz","year":"2013","journal-title":"Expert Opin Ther Targets"},{"key":"B32","doi-asserted-by":"publisher","first-page":"2000018","DOI":"10.1183\/13993003.00018-2020","article-title":"Profibrotic function of pulmonary group 2 innate lymphoid cells is controlled by regnase-1","volume":"57","author":"Nakatsuka","year":"2021","journal-title":"Eur Respir J"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.553859","article-title":"O-Glcnac transferase is critical for transducin-like enhancer of split (Tle)-mediated repression of canonical wnt signaling","volume":"289","author":"Wu","year":"2014","journal-title":"J Biol Chem"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108328","article-title":"Nr4a1 and Nr4a3 reporter mice are differentially sensitive to T cell receptor signal strength and duration","volume":"33","author":"Jennings","year":"2020","journal-title":"Cell Rep"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1007\/s11427-022-2127-2","article-title":"Identification of two migratory colon Ilc2 populations differentially expressing il-17a and il-5\/Il-13","volume":"66","author":"Liu","year":"2023","journal-title":"Sci China Life Sci"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.01.015","article-title":"Single-cell gene expression analyses reveal heterogeneous responsiveness of fetal innate lymphoid progenitors to notch signaling","volume":"14","author":"Chea","year":"2016","journal-title":"Cell Rep"},{"key":"B37","doi-asserted-by":"publisher","first-page":"jem.20182293","DOI":"10.1084\/jem.20182293","article-title":"Single-cell analysis of ror\u03b1 tracer mouse lung reveals ilc progenitors and effector Ilc2 subsets","volume":"217","author":"Ghaedi","year":"2020","journal-title":"J Exp Med"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/nature13979","article-title":"Deubiquitinase duba is a post-translational brake on interleukin-17 production in T cells","volume":"518","author":"Rutz","year":"2015","journal-title":"Nature"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20190490","article-title":"Klrg1 and Nkp46 discriminate subpopulations of human Cd117(+)Crth2(-) ilcs biased toward Ilc2 or Ilc3","volume":"216","author":"Nagasawa","year":"2019","journal-title":"J Exp Med"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1126\/science.1249288","article-title":"Microbiota-dependent crosstalk between macrophages and Ilc3 promotes intestinal homeostasis","volume":"343","author":"Mortha","year":"2014","journal-title":"Science"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-019-0200-x","article-title":"Ilc3-derived Ox40l is essential for homeostasis of intestinal tregs in immunodeficient mice","volume":"17","author":"Deng","year":"2020","journal-title":"Cell Mol Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-00574-8","article-title":"Single-cell profiling reveals the trajectories of natural killer cell differentiation in bone marrow and a stress signature induced by acute myeloid leukemia","volume":"18","author":"Crinier","year":"2021","journal-title":"Cell Mol Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019000699","article-title":"Diversity of peripheral blood human nk cells identified by single-cell rna sequencing","volume":"4","author":"Smith","year":"2020","journal-title":"Blood Adv"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20151750","article-title":"Il-12 drives functional plasticity of human group 2 innate lymphoid cells","volume":"213","author":"Lim","year":"2016","journal-title":"J Exp Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201848075","article-title":"Suppression of aiolos and ikaros expression by lenalidomide reduces human Ilc3-Ilc1\/Nk cell transdifferentiation","volume":"49","author":"Mazzurana","year":"2019","journal-title":"Eur J Immunol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0201-4","article-title":"Tissue signals imprint Ilc2 identity with anticipatory function","volume":"19","author":"Ricardo-Gonzalez","year":"2018","journal-title":"Nat Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.877005","article-title":"Tissue resident and migratory group 2 innate lymphoid cells","volume":"13","author":"Math\u00e4","year":"2022","journal-title":"Front Immunol"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1086","DOI":"10.1016\/j.cell.2017.02.021","article-title":"Systemic human ilc precursors provide a substrate for tissue ilc differentiation","volume":"168","author":"Lim","year":"2017","journal-title":"Cell"},{"key":"B49","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.jaci.2019.01.027","article-title":"Activation of group 2 innate lymphoid cells after allergen challenge in asthmatic patients","volume":"144","author":"Winkler","year":"2019","journal-title":"J Allergy Clin Immunol"},{"key":"B50","doi-asserted-by":"publisher","first-page":"992","DOI":"10.1038\/s41590-019-0423-0","article-title":"C-Kit-Positive Ilc2s exhibit an Ilc3-like signature that may contribute to il-17-Mediated pathologies","volume":"20","author":"Bernink","year":"2019","journal-title":"Nat Immunol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201545598","article-title":"Group 3 innate lymphoid cells (Ilc3s): Origin, differentiation, and plasticity in humans and mice","volume":"45","author":"Montaldo","year":"2015","journal-title":"Eur J Immunol"},{"key":"B52","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1016\/j.immuni.2018.04.028","article-title":"Human innate lymphoid cell subsets possess tissue-type based heterogeneity in phenotype and frequency","volume":"48","author":"Simoni","year":"2018","journal-title":"Immunity"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201899595","article-title":"Stat4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation","volume":"38","author":"Zhang","year":"2019","journal-title":"EMBO J"},{"key":"B54","doi-asserted-by":"publisher","first-page":"5015","DOI":"10.1016\/j.cell.2021.07.029","article-title":"Dysregulation of Ilc3s unleashes progression and immunotherapy resistance in colon cancer","volume":"184","author":"Goc","year":"2021","journal-title":"Cell"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1002\/eji.202048696","article-title":"Identification of human cytotoxic Ilc3s","volume":"51","author":"Krabbendam","year":"2021","journal-title":"Eur J Immunol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2017008839","article-title":"Interleukins 12 and 15 induce cytotoxicity and early nk-cell differentiation in type 3 innate lymphoid cells","volume":"1","author":"Raykova","year":"2017","journal-title":"Blood Adv"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3368","article-title":"The heterogeneity of human Cd127(+) innate lymphoid cells revealed by single-cell rna sequencing","volume":"17","author":"Bj\u00f6rklund","year":"2016","journal-title":"Nat Immunol"},{"key":"B58","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s40348-016-0055-5","article-title":"Lung epithelial gm-csf improves host defense function and epithelial repair in influenza virus pneumonia-a new therapeutic strategy","volume":"3","author":"R\u00f6sler","year":"2016","journal-title":"Mol Cell Pediatr"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1127413\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,7]],"date-time":"2023-03-07T06:16:51Z","timestamp":1678169811000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1127413\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,7]]},"references-count":58,"alternative-id":["10.3389\/fimmu.2023.1127413"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1127413","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,7]]},"article-number":"1127413"}}