Intestinal T cells and group 3 innate lymphoid cells (ILC3 cells) control the composition of the microbiota and gut immune responses. Within the gut, ILC3 subsets coexist that either express or lack the natural cytoxicity receptor (NCR) NKp46. We identified here the transcriptional signature associated with the transcription factor T-bet–dependent differentiation of NCR ILC3 cells into NCR+ ILC3 cells. Contrary to the prevailing view, we found by conditional deletion of the key ILC3 genes Stat3, Il22, Tbx21 and Mcl1 that NCR+ ILC3 cells were redundant for the control of mouse colonic infection with Citrobacter rodentium in the presence of T cells. However, NCR+ ILC3 cells were essential for cecal homeostasis. Our data show that interplay between intestinal ILC3 cells and adaptive lymphocytes results in robust complementary failsafe mechanisms that ensure gut homeostasis.

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We thank M. Camilleri, J. Vella, E. Loza and L. Inglis and the staff of the animal and flow cytometry facilities of The Walter and Eliza Hall Institute of Medical Research and the Centre d'Immunologie de Marseille-Luminy for technical assistance; S. Kaech (Yale University) for mice with loxP-flanked alleles encoding T-bet; and L. Chasson and C. Laprie (Centre d'Immunologie de Marseille-Luminy) for expertise in histology and for assigning scores to tissue sections. Supported by the National Health and Medical Research Council of Australia (G.T.B., Se.C. and N.H.; Dora Lush Postgraduate Research Scholarship to L.C.R.); the Australian Research Council (Future Fellowship to G.T.B.); the Victorian State Government Operational Infrastructure Support and Australian Government National Health and Medical Research Council Independent Research Institutes Infrustructure Support; the European Research Council (THINK Advanced Grant), the Ligue Nationale contre le Cancer (Equipe Labellisée), INSERM, CNRS and Aix-Marseille University to Centre d'Immunologie de Marseille-Luminy (all for the E.V. laboratory); and the Institut Universitaire de France (E.V.).

Author information

Author notes

    • Lucille C Rankin

    Present address: Weill Cornell Medical College, Cornell University, New York, New York, USA.

    • Lucille C Rankin
    •  & Mathilde J H Girard-Madoux

    These authors contributed equally to this work.

    • Gabrielle T Belz
    •  & Eric Vivier

    These authors jointly directed this work.


  1. The Walter and Eliza Hall Institute of Medical Research, and Department of Medical Biology, University of Melbourne, Parkville, Australia.

    • Lucille C Rankin
    • , Cyril Seillet
    • , Lisa A Mielke
    • , Tracy Putoczki
    • , Anthony T Papenfuss
    • , Gordon K Smyth
    • , Sebastian Carotta
    • , Wei Shi
    • , Nicholas D Huntington
    •  & Gabrielle T Belz
  2. Department of Medical Biology, University of Melbourne, Parkville, Australia.

    • Lucille C Rankin
    • , Cyril Seillet
    • , Lisa A Mielke
    • , Tracy Putoczki
    • , Anthony T Papenfuss
    • , Gordon K Smyth
    • , Sebastian Carotta
    • , Wei Shi
    • , Nicholas D Huntington
    •  & Gabrielle T Belz
  3. Centre d'Immunologie de Marseille-Luminy, Université d'Aix-Marseille UM2, Inserm, U1104, CNRS UMR7280, Marseille, France.

    • Mathilde J H Girard-Madoux
    • , Yann Kerdiles
    • , Aurore Fenis
    • , Elisabeth Wieduwild
    • , Sophie Ugolini
    •  & Eric Vivier
  4. Labex Milieu Intérieur, Institut Pasteur, Paris, France.

    • Stanislas Mondot
  5. Laboratoire d'Immunologie and Inserm U932, Institut Curie, Paris, France.

    • Olivier Lantz
  6. Inflammation Research Center, VIB, Ghent University, Ghent, Belgium.

    • Dieter Demon
    •  & Mohamed Lamkanfi
  7. Department of Biochemistry, Ghent University, Ghent, Belgium.

    • Dieter Demon
    •  & Mohamed Lamkanfi
  8. Department of Mathematics and Statistics, University of Melbourne, Parkville, Australia.

    • Gordon K Smyth
  9. Boehringer-Ingelheim RCV, Vienna, Austria.

    • Sebastian Carotta
  10. Ludwig Institute for Cancer Research and Experimental Medicine Unit, Catholic University of Louvain, Brussels, Belgium.

    • Jean-Christophe Renauld
  11. Department of Computing and Information Systems, University of Melbourne, Parkville, Australia.

    • Wei Shi
  12. MI-mAbs consortium Aix-Marseille University, Centre d'Immunologie de Marseille-Luminy, Marseille, France.

    • Sabrina Carpentier
  13. Bioinnovation, SANOFI, Boston, Massachusetts, USA.

    • Tim Soos
    •  & Christopher Arendt
  14. Immunologie, Hôpital de la Conception, Assistance Publique–Hôpitaux de Marseille, Marseille, France.

    • Eric Vivier


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C.S., L.A.M. and Y.K. contributed equally to this work; L.C.R., M.J.H.G.-M., C.S., L.A.M. and Y.K. designed the research, performed experiments and analyzed the data; A.F., E.W., S.M., L.M., J.G., T.P. and A.T.P. performed experiments and analyzed the data; W.S. and G.K.S. performed bioinformatics analyses of RNA-seq data; O.L., D.D., M.L., J.-C.R., C.A., S.U., Se.C. and N.D.H. provided reagents; and G.T.B. and E.V. designed the research, supervised the study, and wrote the manuscript with the help of the other co-authors.

Competing interests

E.V. is a cofounder and shareholder of Innate Pharma, and T.S. and C.A. are employees of Sanofi.

Corresponding authors

Correspondence to Gabrielle T Belz or Eric Vivier.

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