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PMID: 22101730 Published · epublish English Journal Article Research Support, N.I.H., Extramural

AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch.

Nature immunology ·Vol. 13 ·No. 2 ·2011-11-20 ·Pages 144-51

Lee JS, Cella M, McDonald KG, Garlanda C, Kennedy GD, Nukaya M, Mantovani A, Kopan R, Bradfield CA, Newberry RD, Colonna M

Abstract

Innate lymphoid cells (ILCs) of the ILC22 type protect the intestinal mucosa from infection by secreting interleukin 22 (IL-22). ILC22 cells include NKp46(+) and lymphoid tissue-inducer (LTi)-like subsets that express the aryl hydrocarbon receptor (AHR). Here we found that Ahr(-/-) mice had a considerable deficit in ILC22 cells that resulted in less secretion of IL-22 and inadequate protection against intestinal bacterial infection. Ahr(-/-) mice also lacked postnatally 'imprinted' cryptopatches and isolated lymphoid follicles (ILFs), but not embryonically 'imprinted' Peyer's patches. AHR induced the transcription factor Notch, which was required for NKp46(+) ILCs, whereas LTi-like ILCs, cryptopatches and ILFs were partially dependent on Notch signaling. Thus, AHR was essential for ILC22 cells and postnatal intestinal lymphoid tissues. Moreover, ILC22 subsets were heterogeneous in their requirement for Notch and their effect on the generation of intestinal lymphoid tissues.

MeSH Terms
Animals Antigens, Ly/metabolism Female Gastrointestinal Tract/immunology,metabolism Interleukins/genetics,immunology,metabolism Lymphoid Tissue/immunology,metabolism Male Mice Mice, Inbred C57BL Mice, Transgenic Natural Cytotoxicity Triggering Receptor 1/metabolism Receptor, Notch1/metabolism Receptor, Notch2/metabolism Receptors, Aryl Hydrocarbon/metabolism Signal Transduction/immunology
Chemicals
Antigens, Ly Interleukins Natural Cytotoxicity Triggering Receptor 1 Ncr1 protein, mouse Notch1 protein, mouse Notch2 protein, mouse Receptor, Notch1 Receptor, Notch2 Receptors, Aryl Hydrocarbon interleukin-22
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Lee Jacob S
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
Cella Marina
McDonald Keely G
Garlanda Cecilia
Kennedy Gregory D
Nukaya Manabu
Mantovani Alberto
Kopan Raphael
Bradfield Christopher A
Newberry Rodney D
Colonna Marco
References (50)
50 references, click to expand
  1. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation.
    Cell. 2011 Oct 28;147(3):629-40 PMID: 21999944
  2. Integration of genome-wide computation DRE search, AhR ChIP-chip and gene expression analyses of TCDD-elicited responses in the mouse liver.
    BMC Genomics. 2011 Jul 15;12:365 PMID: 21762485
  3. Alpha4beta7/MAdCAM-1 interactions play an essential role in transitioning cryptopatches into isolated lymphoid follicles and a nonessential role in cryptopatch formation.
    J Immunol. 2008 Sep 15;181(6):4052-61 PMID: 18768861
  4. IL-7 and IL-15 independently program the differentiation of intestinal CD3-NKp46+ cell subsets from Id2-dependent precursors.
    J Exp Med. 2010 Feb 15;207(2):273-80 PMID: 20142427
  5. Notch signaling is necessary for adult, but not fetal, development of RORγt(+) innate lymphoid cells.
    Nat Immunol. 2011 Sep 11;12(10):949-58 PMID: 21909092
  6. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells.
    J Immunol. 2010 Sep 15;185(6):3190-8 PMID: 20720200
  7. Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22.
    J Exp Med. 2009 Jan 16;206(1):35-41 PMID: 19114665
  8. The biological functions of T helper 17 cell effector cytokines in inflammation.
    Immunity. 2008 Apr;28(4):454-67 PMID: 18400188
  9. RORγt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota.
    Nat Immunol. 2011 Apr;12(4):320-6 PMID: 21336274
  10. Lineage relationship analysis of RORgammat+ innate lymphoid cells.
    Science. 2010 Oct 29;330(6004):665-9 PMID: 20929731
  11. Interleukin-1beta selectively expands and sustains interleukin-22+ immature human natural killer cells in secondary lymphoid tissue.
    Immunity. 2010 Jun 25;32(6):803-14 PMID: 20620944
  12. Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism.
    Proc Natl Acad Sci U S A. 2010 Nov 16;107(46):19961-6 PMID: 21041655
  13. Immune adaptations that maintain homeostasis with the intestinal microbiota.
    Nat Rev Immunol. 2010 Mar;10(3):159-69 PMID: 20182457
  14. Regulated expression of nuclear receptor RORγt confers distinct functional fates to NK cell receptor-expressing RORγt(+) innate lymphocytes.
    Immunity. 2010 Nov 24;33(5):736-51 PMID: 21093318
  15. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology.
    Nature. 2010 Apr 29;464(7293):1371-5 PMID: 20393462
  16. The aryl hydrocarbon receptor in immunity.
    Trends Immunol. 2009 Sep;30(9):447-54 PMID: 19699679
  17. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens.
    Nat Med. 2008 Mar;14(3):282-9 PMID: 18264109
  18. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling.
    Nat Immunol. 2011 Jan;12(1):21-7 PMID: 21113163
  19. The search for endogenous activators of the aryl hydrocarbon receptor.
    Chem Res Toxicol. 2008 Jan;21(1):102-16 PMID: 18076143
  20. Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor.
    Nature. 2008 May 1;453(7191):65-71 PMID: 18362915
  21. Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells.
    Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9721-6 PMID: 18607004
  22. Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor.
    Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5943-8 PMID: 20231432
  23. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor.
    Nature. 2011 Oct 05;478(7368):197-203 PMID: 21976023
  24. Notch-Hes1 pathway is required for the development of IL-17-producing γδ T cells.
    Blood. 2011 Jul 21;118(3):586-93 PMID: 21606479
  25. The aryl hydrocarbon receptor: a perspective on potential roles in the immune system.
    Immunology. 2009 Jul;127(3):299-311 PMID: 19538249
  26. Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin.
    Nat Immunol. 2009 Jan;10(1):75-82 PMID: 19029904
  27. Notch signaling regulates mouse and human Th17 differentiation.
    J Immunol. 2011 Jul 15;187(2):692-701 PMID: 21685328
  28. CCR6 identifies lymphoid tissue inducer cells within cryptopatches.
    Clin Exp Immunol. 2010 Jun;160(3):440-9 PMID: 20148914
  29. AHR-mediated immunomodulation: the role of altered gene transcription.
    Biochem Pharmacol. 2009 Feb 15;77(4):746-60 PMID: 19100241
  30. External influences on the immune system via activation of the aryl hydrocarbon receptor.
    Semin Immunol. 2011 Apr;23(2):99-105 PMID: 21288737
  31. Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells.
    J Exp Med. 2009 Jan 16;206(1):43-9 PMID: 19114668
  32. Microbial control of regulatory and effector T cell responses in the gut.
    Curr Opin Immunol. 2010 Feb;22(1):63-72 PMID: 20171861
  33. The development of intestinal lymphoid tissues at the interface of self and microbiota.
    Mucosal Immunol. 2009 Nov;2(6):478-85 PMID: 19741595
  34. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity.
    Nature. 2009 Feb 5;457(7230):722-5 PMID: 18978771
  35. IL-17 and Th17 Cells.
    Annu Rev Immunol. 2009;27:485-517 PMID: 19132915
  36. The role of the nuclear hormone receptor RORgammat in the development of lymph nodes and Peyer's patches.
    Immunol Rev. 2003 Oct;195:81-90 PMID: 12969312
  37. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins.
    Nature. 2008 May 1;453(7191):106-9 PMID: 18362914
  38. Identification of multiple isolated lymphoid follicles on the antimesenteric wall of the mouse small intestine.
    J Immunol. 2002 Jan 1;168(1):57-64 PMID: 11751946
  39. Induction of intestinal lymphoid tissue formation by intrinsic and extrinsic signals.
    Semin Immunopathol. 2009 Jul;31(2):151-69 PMID: 19506873
  40. The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27.
    Nat Immunol. 2010 Sep;11(9):854-61 PMID: 20676095
  41. Comparative toxicogenomic analysis of the hepatotoxic effects of TCDD in Sprague Dawley rats and C57BL/6 mice.
    Toxicol Sci. 2006 Dec;94(2):398-416 PMID: 16960034
  42. IL-22 bridges the lymphotoxin pathway with the maintenance of colonic lymphoid structures during infection with Citrobacter rodentium.
    Nat Immunol. 2011 Aug 28;12(10):941-8 PMID: 21874025
  43. Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense.
    Immunity. 2008 Dec 19;29(6):958-70 PMID: 19084435
  44. An innately dangerous balancing act: intestinal homeostasis, inflammation, and colitis-associated cancer.
    J Exp Med. 2010 Aug 2;207(8):1573-7 PMID: 20679404
  45. IL-22 and inflammation: leukin' through a glass onion.
    Eur J Immunol. 2008 Dec;38(12):3265-8 PMID: 19016525
  46. 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
  47. Regulation of T cell activation by Notch ligand, DLL4, promotes IL-17 production and Rorc activation.
    J Immunol. 2009 Jun 15;182(12):7381-8 PMID: 19494260
  48. An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis.
    Proc Natl Acad Sci U S A. 2010 Nov 30;107(48):20768-73 PMID: 21068375
  49. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22.
    Nat Immunol. 2011 May;12(5):383-90 PMID: 21502992
  50. New insights into the development of lymphoid tissues.
    Nat Rev Immunol. 2010 Sep;10(9):664-74 PMID: 20706277
Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2916
DOI
10.1038/ni.2187
Published
2011-11-20
Epub
2011-00-20
Pages
144-51
Language
English
Region
United States
NLM ID
100941354
PMCID
PMC3468413
Subset
IM
Grants
NIDDK NIH HHS · P30DK052574 · United States
NIEHS NIH HHS · K08 ES017283 · United States
NIDCR NIH HHS · R01 DE021255-01 · United States
NIEHS NIH HHS · R01 ES005703 · United States
NIGMS NIH HHS · R01 GM055479 · United States
NIDDK NIH HHS · R01 DK064798-08 · United States
NIDDK NIH HHS · P30 DK020579 · United States
PHS HHS · A1067854 · United States
NIDDK NIH HHS · P30 DK052574 · United States
NIDCR NIH HHS · R01 DE021255 · United States
NIDDK NIH HHS · R01 DK064798 · United States
Corrections
CommentIn
PMID: 22261961
External Links
PubMed source DOI: 10.1038/ni.2187 PMC Full Text View journal details
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