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

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.

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Figure 1: AHR is essential for IL-22-production in the intestinal lamina propria and resistance to C. rodentium infection.
Figure 2: Ahr−/− mice have considerably fewer NKp46+ ILCs.
Figure 3: Ahr−/− mice lack CD4+ LTi-like ILCs as well as cryptopatches and ILFs in the small intestine.
Figure 4: The developmental defect of Ahr−/− mice is cell intrinsic.
Figure 5: AHR activation induces the upregulation of Notch.
Figure 6: Mice that selectively lack expression of RBP-Jκ in the hematopoietic compartment have fewer NKp46+ ILCs.

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Acknowledgements

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.).

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J.S.L., M.Ce. and K.G.M. did experiments; C.G., G.D.K., M.N., A.M., R.K., C.A.B. provided reagents and experimental advice; J.S.L., M.Ce., R.D.N and M.Co. designed experiments and analyzed data; M.Co. supervised research; and J.S.L. and M.Co. wrote the manuscript.

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Correspondence to Marco Colonna.

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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

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