Home LiteratureArticle Details
PMID: 19029905 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells.

Nature immunology ·Vol. 10 ·No. 1 ·2009-01-00 ·Pages 66-74

Cupedo T, Crellin NK, Papazian N, Rombouts EJ, Weijer K, Grogan JL, Fibbe WE, Cornelissen JJ, Spits H

Abstract

The human body contains over 500 individual lymph nodes, yet the biology of their formation is poorly understood. Here we identify human lymphoid tissue-inducer cells (LTi cells) as lineage-negative RORC+ CD127+ cells with the functional ability to interact with mesenchymal cells through lymphotoxin and tumor necrosis factor. Human LTi cells were committed natural killer (NK) cell precursors that produced interleukin 17 (IL-17) and IL-22. In vitro, LTi cells gave rise to RORC+ CD127+ NK cells that retained the ability to produce IL-17 and IL-22. Postnatally, similar populations of LTi cell-like cells and RORC+ CD127+ NK cells were present in tonsils, and both secreted IL-17 and IL-22 but no interferon-gamma. Our data indicate that lymph node organogenesis is controlled by an NK cell precursor population with adaptive immune features and demonstrate a previously unappreciated link between the innate and adaptive immune systems.

MeSH Terms
Animals CD56 Antigen/metabolism Cell Differentiation Cells, Cultured Humans Immunity, Cellular Immunity, Innate Interferon-gamma/biosynthesis Interleukin-17/biosynthesis Interleukin-7 Receptor alpha Subunit/immunology Interleukins/biosynthesis Lymph Nodes/cytology,embryology,immunology Lymphoid Tissue/embryology,immunology Lymphotoxin-alpha/immunology Mesentery/embryology,immunology Mice Natural Killer T-Cells/immunology Nuclear Receptor Subfamily 1, Group F, Member 3 Organogenesis Palatine Tonsil/cytology,immunology Precursor Cells, T-Lymphoid/immunology Receptors, Retinoic Acid/immunology Receptors, Thyroid Hormone/immunology Spleen/embryology,immunology
Chemicals
CD56 Antigen Interleukin-17 Interleukin-7 Receptor alpha Subunit Interleukins Lymphotoxin-alpha Nuclear Receptor Subfamily 1, Group F, Member 3 RORC protein, human Receptors, Retinoic Acid Receptors, Thyroid Hormone Rorc protein, mouse Interferon-gamma interleukin-22
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Cupedo Tom
Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands. t.cupedo@erasmusmc.nl
Crellin Natasha K
Papazian Natalie
Rombouts Elwin J
Weijer Kees
Grogan Jane L
Fibbe Willem E
Cornelissen Jan J
Spits Hergen
References (42)
42 references, click to expand
  1. The fetal liver counterpart of adult common lymphoid progenitors gives rise to all lymphoid lineages, CD45+CD4+CD3- cells, as well as macrophages.
    J Immunol. 2001 Jun 1;166(11):6593-601 PMID: 11359812
  2. ROR gamma: the third member of ROR/RZR orphan receptor subfamily that is highly expressed in skeletal muscle.
    Biochem Biophys Res Commun. 1994 Dec 30;205(3):1976-83 PMID: 7811290
  3. Retinoid-related orphan receptor gamma (RORgamma) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis.
    Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):10132-7 PMID: 10963675
  4. Human natural killer cell development.
    Immunol Rev. 2006 Dec;214:56-72 PMID: 17100876
  5. Evidence for discrete stages of human natural killer cell differentiation in vivo.
    J Exp Med. 2006 Apr 17;203(4):1033-43 PMID: 16606675
  6. The biological functions of T helper 17 cell effector cytokines in inflammation.
    Immunity. 2008 Apr;28(4):454-67 PMID: 18400188
  7. IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes.
    J Immunol. 2005 Mar 15;174(6):3695-702 PMID: 15749908
  8. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells.
    Cell. 2006 Sep 22;126(6):1121-33 PMID: 16990136
  9. Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2.
    Nature. 1999 Feb 25;397(6721):702-6 PMID: 10067894
  10. Interleukin-17 stimulates the expression of interleukin-8, growth-related oncogene-alpha, and granulocyte-colony-stimulating factor by human airway epithelial cells.
    Am J Respir Cell Mol Biol. 2002 Jun;26(6):748-53 PMID: 12034575
  11. The development of gut associated lymphoid tissue in the terminal ileum of fetal human intestine.
    Clin Exp Immunol. 1986 Jun;64(3):536-43 PMID: 3491695
  12. Delta-like1-induced Notch1 signaling regulates the human plasmacytoid dendritic cell versus T-cell lineage decision through control of GATA-3 and Spi-B.
    Blood. 2006 Mar 15;107(6):2446-52 PMID: 16317090
  13. Thyroid autoimmune disease: demonstration of thyroid antigen-specific B cells and recombination-activating gene expression in chemokine-containing active intrathyroidal germinal centers.
    Am J Pathol. 2001 Sep;159(3):861-73 PMID: 11549579
  14. Requirement for RORgamma in thymocyte survival and lymphoid organ development.
    Science. 2000 Jun 30;288(5475):2369-73 PMID: 10875923
  15. The evolutionary history of lymphoid organs.
    Nat Immunol. 2007 Feb;8(2):131-5 PMID: 17242686
  16. The transcription factor Spi-B is expressed in plasmacytoid DC precursors and inhibits T-, B-, and NK-cell development.
    Blood. 2003 Feb 1;101(3):1015-23 PMID: 12393575
  17. Naive T cell recruitment to nonlymphoid tissues: a role for endothelium-expressed CC chemokine ligand 21 in autoimmune disease and lymphoid neogenesis.
    J Immunol. 2003 May 1;170(9):4638-48 PMID: 12707342
  18. The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis.
    J Immunol. 2007 Feb 15;178(4):2229-40 PMID: 17277128
  19. Initiation of cellular organization in lymph nodes is regulated by non-B cell-derived signals and is not dependent on CXC chemokine ligand 13.
    J Immunol. 2004 Oct 15;173(8):4889-96 PMID: 15470030
  20. Inflammation, a prototype for organogenesis of the lymphopoietic/hematopoietic system.
    Curr Opin Immunol. 2000 Jun;12(3):342-5 PMID: 10781400
  21. Organogenesis of lymphoid tissues.
    Nat Rev Immunol. 2003 Apr;3(4):292-303 PMID: 12669020
  22. Lymph node pathology in primary combined immunodeficiency diseases.
    Springer Semin Immunopathol. 1998;19(4):459-78 PMID: 9618768
  23. Restoration of lymphoid organ integrity through the interaction of lymphoid tissue-inducer cells with stroma of the T cell zone.
    Nat Immunol. 2008 Jun;9(6):667-75 PMID: 18425132
  24. Lymphoid neogenesis in chronic inflammatory diseases.
    Nat Rev Immunol. 2006 Mar;6(3):205-17 PMID: 16498451
  25. Role of IL-17A, IL-17F, and the IL-17 receptor in regulating growth-related oncogene-alpha and granulocyte colony-stimulating factor in bronchial epithelium: implications for airway inflammation in cystic fibrosis.
    J Immunol. 2005 Jul 1;175(1):404-12 PMID: 15972674
  26. Mature natural killer cell and lymphoid tissue-inducing cell development requires Id2-mediated suppression of E protein activity.
    J Exp Med. 2007 May 14;204(5):1119-30 PMID: 17452521
  27. Normal development of human fetal hematopoiesis between eight and seventeen weeks' gestation.
    Am J Obstet Gynecol. 2000 Oct;183(4):1029-34 PMID: 11035358
  28. Human Peyer's patches: an immunohistochemical study.
    Gut. 1986 Apr;27(4):405-10 PMID: 3514387
  29. Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain.
    Immunity. 1995 Mar;2(3):223-38 PMID: 7697543
  30. IL-22 increases the innate immunity of tissues.
    Immunity. 2004 Aug;21(2):241-54 PMID: 15308104
  31. Mesenchymal stem cells in human second-trimester bone marrow, liver, lung, and spleen exhibit a similar immunophenotype but a heterogeneous multilineage differentiation potential.
    Haematologica. 2003 Aug;88(8):845-52 PMID: 12935972
  32. Developmental defects of lymphoid cells in Jak3 kinase-deficient mice.
    Immunity. 1995 Dec;3(6):771-82 PMID: 8777722
  33. Role of T and NK cells and IL7/IL7r interactions during neonatal maturation of lymph nodes.
    Proc Natl Acad Sci U S A. 2006 Sep 5;103(36):13457-62 PMID: 16938836
  34. The development of the human lymph node.
    Cell Tissue Res. 1982;225(2):387-413 PMID: 6980711
  35. Different cytokines induce surface lymphotoxin-alphabeta on IL-7 receptor-alpha cells that differentially engender lymph nodes and Peyer's patches.
    Immunity. 2002 Dec;17(6):823-33 PMID: 12479827
  36. A human CD34(+) subset resides in lymph nodes and differentiates into CD56bright natural killer cells.
    Immunity. 2005 Mar;22(3):295-304 PMID: 15780987
  37. Lymphoid organ development: from ontogeny to neogenesis.
    Nat Immunol. 2006 Apr;7(4):344-53 PMID: 16550197
  38. An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells.
    Nat Immunol. 2004 Jan;5(1):64-73 PMID: 14691482
  39. Development of lymphoid tissues in the human embryo and early fetus.
    Arch Pathol. 1970 Oct;90(4):348-53 PMID: 5466692
  40. RORgammat and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells.
    Nat Immunol. 2009 Jan;10(1):83-91 PMID: 19029903
  41. Developing lymph nodes collect CD4+CD3- LTbeta+ cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells.
    Immunity. 1997 Oct;7(4):493-504 PMID: 9354470
  42. Inhibition, by vinca alkaloids and colchicine, of antigenic modulation induced by anti-CD19 monoclonal antibodies.
    Leuk Res. 1988;12(2):135-41 PMID: 3282129
Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2916
DOI
10.1038/ni.1668
Email
t.cupedo@erasmusmc.nl
Published
2009-01-00
Epub
2008-00-23
Pages
66-74
Language
English
Region
United States
NLM ID
100941354
Subset
IM
Corrections
CommentIn
PMID: 19088733
External Links
PubMed source DOI: 10.1038/ni.1668 View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2