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.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Hooper, L.V. & Macpherson, A.J. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat. Rev. Immunol. 10, 159–169 (2010).
Asquith, M. & Powrie, F. An innately dangerous balancing act: intestinal homeostasis, inflammation, and colitis-associated cancer. J. Exp. Med. 207, 1573–1577 (2010).
Hand, T. & Belkaid, Y. Microbial control of regulatory and effector T cell responses in the gut. Curr. Opin. Immunol. 22, 63–72 (2010).
Eberl, G. & Lochner, M. The development of intestinal lymphoid tissues at the interface of self and microbiota. Mucosal Immunol. 2, 478–485 (2009).
Ouyang, W., Kolls, J.K. & Zheng, Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28, 454–467 (2008).
Zenewicz, L.A. & Flavell, R.A. IL-22 and inflammation: leukin' through a glass onion. Eur. J. Immunol. 38, 3265–3268 (2008).
Zheng, Y. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat. Med. 14, 282–289 (2008).
Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V.K. IL-17 and Th17 cells. Annu. Rev. Immunol. 27, 485–517 (2009).
Sonnenberg, G.F., Fouser, L.A. & Artis, D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat. Immunol. 12, 383–390 (2011).
Spits, H. & Di Santo, J.P. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat. Immunol. 12, 21–27 (2011).
van de Pavert, S.A. & Mebius, R.E. New insights into the development of lymphoid tissues. Nat. Rev. Immunol. 10, 664–674 (2010).
Sawa, S. et al. Lineage relationship analysis of RORγt+ innate lymphoid cells. Science 330, 665–669 (2010).
Takatori, H. et al. Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J. Exp. Med. 206, 35–41 (2009).
Buonocore, S. et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371–1375 (2010).
Eberl, G. & Littman, D.R. The role of the nuclear hormone receptor RORγt in the development of lymph nodes and Peyer's patches. Immunol. Rev. 195, 81–90 (2003).
Satoh-Takayama, N. et al. Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 29, 958–970 (2008).
Satoh-Takayama, N. et al. IL-7 and IL-15 independently program the differentiation of intestinal CD3−NKp46+ cell subsets from Id2-dependent precursors. J. Exp. Med. 207, 273–280 (2010).
Sanos, S.L. et al. RORγt and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nat. Immunol. 10, 83–91 (2009).
Cella, M. et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 457, 722–725 (2009).
Stockinger, B., Hirota, K., Duarte, J. & Veldhoen, M. External influences on the immune system via activation of the aryl hydrocarbon receptor. Semin. Immunol. 23, 99–105 (2011).
Kerkvliet, N.I. AHR-mediated immunomodulation: the role of altered gene transcription. Biochem. Pharmacol. 77, 746–760 (2009).
Stevens, E.A., Mezrich, J.D. & Bradfield, C.A. The aryl hydrocarbon receptor: a perspective on potential roles in the immune system. Immunology 127, 299–311 (2009).
Esser, C., Rannug, A. & Stockinger, B. The aryl hydrocarbon receptor in immunity. Trends Immunol. 30, 447–454 (2009).
Nguyen, L.P. & Bradfield, C.A. The search for endogenous activators of the aryl hydrocarbon receptor. Chem. Res. Toxicol. 21, 102–116 (2008).
Li, Y. et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147, 629–640 (2011).
Opitz, C.A. et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197–203 (2011).
Quintana, F.J. et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453, 65–71 (2008).
Nguyen, N.T. et al. Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc. Natl. Acad. Sci. USA 107, 19961–19966 (2010).
Mezrich, J.D. et al. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J. Immunol. 185, 3190–3198 (2010).
Quintana, F.J. et al. An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 107, 20768–20773 (2010).
Apetoh, L. et al. The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat. Immunol. 11, 854–861 (2010).
Veldhoen, M. et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008).
Veldhoen, M., Hirota, K., Christensen, J., O'Garra, A. & Stockinger, B. Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. J. Exp. Med. 206, 43–49 (2009).
Kimura, A., Naka, T., Nohara, K., Fujii-Kuriyama, Y. & Kishimoto, T. Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells. Proc. Natl. Acad. Sci. USA 105, 9721–9726 (2008).
Luci, C. et al. Influence of the transcription factor RORγt on the development of NKp46+ cell populations in gut and skin. Nat. Immunol. 10, 75–82 (2009).
Sawa, S. et al. RORγt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat. Immunol. 12, 320–326 (2011).
Boverhof, D.R. et al. Comparative toxicogenomic analysis of the hepatotoxic effects of TCDD in Sprague Dawley rats and C57BL/6 mice. Toxicol. Sci. 94, 398–416 (2006).
Hughes, T. et al. Interleukin-1β selectively expands and sustains interleukin-22+ immature human natural killer cells in secondary lymphoid tissue. Immunity 32, 803–814 (2010).
Dere, E., Lo, R., Celius, T., Matthews, J. & Zacharewski, T.R. Integration of genome-wide computation DRE search, AhR ChIP-chip and gene expression analyses of TCDD-elicited responses in the mouse liver. BMC Genomics 12, 365 (2011).
Lügering, A. et al. CCR6 identifies lymphoid tissue inducer cells within cryptopatches. Clin. Exp. Immunol. 160, 440–449 (2010).
Hamada, H. et al. Identification of multiple isolated lymphoid follicles on the antimesenteric wall of the mouse small intestine. J. Immunol. 168, 57–64 (2002).
Ota, N. et al. IL-22 bridges the lymphotoxin pathway with the maintenance of colonic lymphoid structures during infection with Citrobacter rodentium. Nat. Immunol. 12, 941–948 (2011).
Shibata, K. et al. Notch-Hes1 pathway is required for the development of IL-17-producing gd T cells. Blood 118, 586–593 (2011).
Mukherjee, S., Schaller, M.A., Neupane, R., Kunkel, S.L. & Lukacs, N.W. Regulation of T cell activation by Notch ligand, DLL4, promotes IL-17 production and Rorc activation. J. Immunol. 182, 7381–7388 (2009).
Keerthivasan, S. et al. Notch signaling regulates mouse and human Th17 differentiation. J. Immunol. 187, 692–701 (2011).
Possot, C. et al. Notch signaling is necessary for adult, but not fetal, development of RORγt+ innate lymphoid cells. Nat. Immunol. 12, 949–958 (2011).
Alam, M.S. et al. Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor. Proc. Natl. Acad. Sci. USA 107, 5943–5948 (2010).
Vonarbourg, C. et al. Regulated expression of nuclear receptor RORγt confers distinct functional fates to NK cell receptor-expressing RORγt+ innate lymphocytes. Immunity 33, 736–751 (2010).
Finke, D. Induction of intestinal lymphoid tissue formation by intrinsic and extrinsic signals. Semin. Immunopathol. 31, 151–169 (2009).
Wang, C., McDonough, J.S., McDonald, K.G., Huang, C. & Newberry, R.D. Alpha4beta7/MAdCAM-1 interactions play an essential role in transitioning cryptopatches into isolated lymphoid follicles and a nonessential role in cryptopatch formation. J. Immunol. 181, 4052–4061 (2008).
We thank S. Gilfillan and P. Ahern for critical comments; R.D. Schreiber (Washington University), T. Honjo (Kyoto University) and A. Tumanov (Trudeau Institute) for mouse strains; J. Gordon (Washington University) for germ-free mice (funded by the National Institute of Diabetes and Digestive and Kidney Disease (Digestive Disease Research Core Center grant P30DK052574)); and D. O'Donnell and M. Karlsson for germ-free husbandry. Supported by the US National Institutes of Health (Kirschstein–National Research Service Award to J.S.L., R01 DE021255-01 to M.Co., and R01 DK064798 to R.D.N.) and the National Institute of Allergy and Infectious Diseases Center for HIV/AIDS Vaccine Immunology (A1067854 to M.Co.).
The authors declare no competing financial interests.
About this article
Cite this article
Lee, J., Cella, M., McDonald, K. et al. AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat Immunol 13, 144–151 (2012). https://doi.org/10.1038/ni.2187
Cellular & Molecular Immunology (2021)
International Immunopharmacology (2021)
Expert Opinion on Biological Therapy (2021)
The role of the intestinal microbiota in allogeneic HCT: clinical associations and preclinical mechanisms
Current Opinion in Genetics & Development (2021)
Immunoregulatory Sensory Circuits in Group 3 Innate Lymphoid Cell (ILC3) Function and Tissue Homeostasis
Frontiers in Immunology (2020)