Systemic Human ILC Precursors Provide a Substrate for Tissue ILC Differentiation

Ai Ing Lim, Yan Li, Silvia Lopez-Lastra, Ralph Stadhouders, Franziska Paul, Armanda Casrouge, Nicolas Serafini, Anne Puel, Jacinta Bustamante, Laura Surace, Guillemette Masse-Ranson, Eyal David, Helene Strick-Marchand, Lionel Le Bourhis, Roberto Cocchi, Davide Topazio, Paolo Graziano, Lucia Anna Muscarella, Lars Rogge, Xavier NorelJean Michel Sallenave, Matthieu Allez, Thomas Graf, Rudi W. Hendriks, Jean Laurent Casanova, Ido Amit, Hans Yssel, James P. Di Santo

Research output: Contribution to journalArticle

Abstract

Innate lymphoid cells (ILCs) represent innate versions of T helper and cytotoxic T cells that differentiate from committed ILC precursors (ILCPs). How ILCPs give rise to mature tissue-resident ILCs remains unclear. Here, we identify circulating and tissue ILCPs in humans that fail to express the transcription factors and cytokine outputs of mature ILCs but have these signature loci in an epigenetically poised configuration. Human ILCPs robustly generate all ILC subsets in vitro and in vivo. While human ILCPs express low levels of retinoic acid receptor (RAR)-related orphan receptor C (RORC) transcripts, these cells are found in RORC-deficient patients and retain potential for EOMES+ natural killer (NK) cells, interferon gamma-positive (IFN-γ+) ILC1s, interleukin (IL)-13+ ILC2s, and for IL-22+, but not for IL-17A+ ILC3s. Our results support a model of tissue ILC differentiation (“ILC-poiesis”), whereby diverse ILC subsets are generated in situ from systemically distributed ILCPs in response to local environmental signals.

Original languageEnglish
Pages (from-to)1086-1100.e10
JournalCell
Volume168
Issue number6
DOIs
Publication statusPublished - Mar 9 2017

Keywords

  • cell fate
  • cytokines
  • development
  • humanized mice
  • innate lymphoid cells
  • lymphopoiesis
  • signaling
  • single cell cloning
  • transcription factors

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Lim, A. I., Li, Y., Lopez-Lastra, S., Stadhouders, R., Paul, F., Casrouge, A., Serafini, N., Puel, A., Bustamante, J., Surace, L., Masse-Ranson, G., David, E., Strick-Marchand, H., Le Bourhis, L., Cocchi, R., Topazio, D., Graziano, P., Muscarella, L. A., Rogge, L., ... Di Santo, J. P. (2017). Systemic Human ILC Precursors Provide a Substrate for Tissue ILC Differentiation. Cell, 168(6), 1086-1100.e10. https://doi.org/10.1016/j.cell.2017.02.021