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Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets

Nature Immunology volume 16, pages 306317 (2015) | Download Citation

Abstract

The recognized diversity of innate lymphoid cells (ILCs) is rapidly expanding. Three ILC classes have emerged, ILC1, ILC2 and ILC3, with ILC1 and ILC3 including several subsets. The classification of some subsets is unclear, and it remains controversial whether natural killer (NK) cells and ILC1 cells are distinct cell types. To address these issues, we analyzed gene expression in ILCs and NK cells from mouse small intestine, spleen and liver, as part of the Immunological Genome Project. The results showed unique gene-expression patterns for some ILCs and overlapping patterns for ILC1 cells and NK cells, whereas other ILC subsets remained indistinguishable. We identified a transcriptional program shared by small intestine ILCs and a core ILC signature. We revealed and discuss transcripts that suggest previously unknown functions and developmental paths for ILCs.

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References

  1. 1.

    & The Immunological Genome Project: networks of gene expression in immune cells. Nat. Immunol. 9, 1091–1094 (2008).

  2. 2.

    , & Development, differentiation, and diversity of innate lymphoid cells. Immunity 41, 354–365 (2014).

  3. 3.

    , & Innate lymphoid cells in inflammation and immunity. Immunity 41, 366–374 (2014).

  4. 4.

    et al. Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell 157, 340–356 (2014).

  5. 5.

    et al. Lineage relationship analysis of RORgammat+ innate lymphoid cells. Science 330, 665–669 (2010).

  6. 6.

    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 (2011).

  7. 7.

    et al. A T-bet gradient controls the fate and function of CCR6-Rorγt+ innate lymphoid cells. Nature 494, 262–265 (2013).

  8. 8.

    et al. Distinct requirements for T-bet in gut innate lymphoid cells. J. Exp. Med. 209, 2331–2338 (2012).

  9. 9.

    et al. The transcription factor T-bet is essential for the development of NKp46+ innate lymphocytes via the Notch pathway. Nat. Immunol. 14, 389–395 (2013).

  10. 10.

    et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371–1375 (2010).

  11. 11.

    , , & A committed precursor to innate lymphoid cells. Nature 508, 397–401 (2014).

  12. 12.

    , & Location and cellular stages of natural killer cell development. Trends Immunol. 34, 573–582 (2013).

  13. 13.

    et al. The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation. Immunity 36, 55–67 (2012).

  14. 14.

    et al. Identity, regulation and in vivo function of gut NKp46+RORγt+ and NKp46+RORγt– lymphoid cells. EMBO J. 30, 2934–2947 (2011).

  15. 15.

    , , , & IL-2-dependent adaptive control of NK cell homeostasis. J. Exp. Med. 210, 1179–1187 (2013).

  16. 16.

    et al. Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-γ-producing cells. Immunity 38, 769–781 (2013).

  17. 17.

    et al. IL-9-mediated survival of type 2 innate lymphoid cells promotes damage control in helminth-induced lung inflammation. J. Exp. Med. 210, 2951–2965 (2013).

  18. 18.

    et al. The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells. Immunity 37, 649–659 (2012).

  19. 19.

    et al. The transcription factor GATA3 is critical for the development of all IL-7Rα-expressing innate lymphoid cells. Immunity 40, 378–388 (2014).

  20. 20.

    & Nuclear receptors, RXR, and the Big Bang. Cell 157, 255–266 (2014).

  21. 21.

    et al. Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science 343, 432–437 (2014).

  22. 22.

    et al. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J. Exp. Med. 210, 535–549 (2013).

  23. 23.

    , & in Cell Adhesion Molecules: Implications in Neurological Diseases, Advances in Neurobiology Vol. 8 (eds. Berezin, V. & Walmod, P.S.) Chapter 8 (Springer Science+Business Media, 2014).

  24. 24.

    et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 457, 722–725 (2009).

  25. 25.

    et al. Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal tolerance. Science 343, 1249288 (2014).

  26. 26.

    et al. Production of granulocyte/macrophage-colony stimulating factor by human natural killer cells. Modulation by the p75 subunit of the interleukin 2 and by the CD2 receptor. J. Clin. Invest. 88, 67–75 (1991).

  27. 27.

    et al. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature 508, 123–127 (2014).

  28. 28.

    et al. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science 334, 1561–1565 (2011).

  29. 29.

    et al. The basic leucine zipper transcription factor E4BP4 is essential for natural killer cell development. Nat. Immunol. 10, 1118–1124 (2009).

  30. 30.

    et al. Nfil3/E4bp4 is required for the development and maturation of NK cells in vivo. J. Exp. Med. 206, 2977–2986 (2009).

  31. 31.

    et al. Nfil3 is required for the development of all innate lymphoid cell subsets. J. Exp. Med. 211, 1733–1740 (2014).

  32. 32.

    et al. Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens. J. Exp. Med. 211, 1723–1731 (2014).

  33. 33.

    et al. Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell 158, 300–313 (2014).

  34. 34.

    , & Identification and distribution of developing innate lymphoid cells in the fetal mouse intestine. Nat. Immunol. (2014).

  35. 35.

    et al. Tyrosine receptor RET is a key regulator of Peyer's patch organogenesis. Nature 446, 547–551 (2007).

  36. 36.

    et al. Gene deregulation and chronic activation in natural killer cells deficient in the transcription factor ETS1. Immunity 36, 921–932 (2012).

  37. 37.

    , , , & Post-transcriptional regulation of gene expression in innate immunity. Nat. Rev. Immunol. 14, 361–376 (2014).

  38. 38.

    & Immunological functions of the neuropillins and plexins as receptors for semaphorins. Nat. Rev. Immunol. 13, 802–814 (2013).

  39. 39.

    et al. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J. Exp. Med. 209, 1713–1722 (2012).

  40. 40.

    et al. Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J. Exp. Med. 209, 1723–1742 (2012).

  41. 41.

    et al. Adaptive immunity to murine skin commensals. Proc. Natl. Acad. Sci. USA 111, E2977–E2986 (2014).

  42. 42.

    et al. T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow. J. Exp. Med. 211, 563–577 (2014).

  43. 43.

    et al. Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells. Elife 3, e01659 (2014).

  44. 44.

    et al. Induction of germline transcription in the Tcrγ locus by Stat5: implications for accessibility control by the IL-7 receptor. Immunity 11, 213–223 (1999).

  45. 45.

    , & Interleukin 15 controls the generation of restricted T cell receptor repertoire of intraepithelial lymphocytes. Nat. Immunol. 6, 1263–1271 (2005).

  46. 46.

    et al. An in vitro model of innate lymphoid cell function and differentiation. Mucosal Immunol. (2014).

  47. 47.

    et al. The basic leucine zipper transcription factor NFIL3 directs the development of a common innate lymphoid cell progenitor. Elife 10, e04406 (2014).

  48. 48.

    et al. The chemokine receptor CXCR6 controls the functional topograophy of interluekin-22 producing intestinal innate lymphoid cells. Immunity 41, 776–788 (2014).

  49. 49.

    et al. ImmGen report: molecular definition of natural killer cell identity and activation. Nat. Immunol. 13, 1000–1009 (2012).

  50. 50.

    et al. Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J. Clin. Invest. 123, 1444–1456 (2013).

  51. 51.

    et al. GenePattern 2.0. Nat. Genet. 38, 500–501 (2006).

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Acknowledgements

We thank our colleagues in the ImmGen consortium, especially C. Benoist and L. Lanier, for input and discussion; the core ImmGen team, K. Rothamel and A. Rhodes, for contributions and technical assistance; M. Artyomov, G. Krishnan and J. Siegel for computational assistance; D. Sojka for discussion; E. Lantelme and D. Brinja for sorting assistance; P. Wang for microscopy assistance; and eBioscience and Affymetrix for support of the ImmGen Project. Supported by the US National Institutes of Health (R24AI072073 to the ImmGen Consortium; 1U01AI095542, R01DE021255 and R21CA16719 to the Colonna laboratory; MSTP T32 GM07200 to M.L.R.; and Infectious Disease Training Grant T32 AI 7172-34 to V.S.C.).

Author information

Affiliations

  1. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Michelle L Robinette
    • , Victor S Cortez
    • , Yaming Wang
    • , Susan Gilfillan
    • , Marco Colonna
    • , Keke Fairfax
    •  & Gwendalyn J Randolph
  2. Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Anja Fuchs
  3. Merck Research Laboratories, Palo Alto, California, USA.

    • Jacob S Lee
  4. Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.

    • Scott K Durum
  5. Division of Biological Sciences, University of California San Diego, La Jolla, California, USA.

    • Laura Shaw
    • , Bingfei Yu
    •  & Ananda Goldrath
  6. Computer Science Department, Stanford University, Stanford, California, USA.

    • Sara Mostafavi
  7. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Aviv Regev
  8. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Edy Y Kim
    • , Dan F Dwyer
    • , Michael B Brenner
    •  & K Frank Austen
  9. Division of Immunology, Department of Microbiology & Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.

    • Andrew Rhoads
    • , Devapregasan Moodley
    • , Hideyuki Yoshida
    • , Diane Mathis
    •  & Christophe Benoist
  10. Department of Microbiology & Immunology, University of California San Francisco, San Francisco, California, USA.

    • Tsukasa Nabekura
    • , Viola Lam
    •  & Lewis L Lanier
  11. Icahn Medical Institute, Mount Sinai Hospital, New York, New York, USA.

    • Brian Brown
    •  & Miriam Merad
  12. Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA and Department of Cancer Immunology, Genentech, San Francisco, California, USA.

    • Viviana Cremasco
    •  & Shannon Turley
  13. Department of Medicine, Boston University, Boston, Massachusetts, USA.

    • Paul Monach
  14. Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA.

    • Michael L Dustin
  15. Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

    • Yuesheng Li
    • , Susan A Shinton
    •  & Richard R Hardy
  16. Department of Life Sciences, Ben-Gurion University of the Negev, Be'er Sheva, Israel.

    • Tal Shay
  17. Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

    • Yilin Qi
    • , Katelyn Sylvia
    •  & Joonsoo Kang

Consortia

  1. the Immunological Genome Consortium

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Contributions

M.L.R. analyzed data; A.F., M.L.R., J.S.L. and Y.W. sorted cell subsets; M.L.R., A.F. and V.S.C. performed follow-up experiments and analyzed data; S.G. maintained mice; S.K.D. provided critical reagents; M.L.R., A.F., S.G. and M.C. designed studies; M.L.R. and M.C. wrote the paper; and the ImmGen Consortium contributed to the experimental design and data collection.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Marco Colonna.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1 and 2

Excel files

  1. 1.

    Supplementary Table 1

    Unique transcripts of individual ILC subsets

  2. 2.

    Supplementary Table 2

    Shared transcripts between siILC subsets

  3. 3.

    Supplementary Table 3

    Transcripts differentially expressed among ILC3 subsets

  4. 4.

    Supplementary Table 4

    Transcripts differentially expressed between NK cells and ILC1 cells in a single tissue

  5. 5.

    Supplementary Table 5

    Transcripts differentially expressed between NK cells and ILC1 cells in two tissues

  6. 6.

    Supplementary Table 6

    Core ILC1 and NK cell signatures

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DOI

https://doi.org/10.1038/ni.3094

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