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Cell. 2017 Mar 9;168(6):1086-1100.e10. doi: 10.1016/j.cell.2017.02.021.

Systemic Human ILC Precursors Provide a Substrate for Tissue ILC Differentiation.

Author information

1
Innate Immunity Unit, Institut Pasteur, 75724 Paris, France; Inserm U1223, 75015 Paris, France; Université Paris-Diderot, Sorbonne Paris Cité, 75205 Paris, France.
2
Innate Immunity Unit, Institut Pasteur, 75724 Paris, France; Inserm U1223, 75015 Paris, France.
3
Innate Immunity Unit, Institut Pasteur, 75724 Paris, France; Inserm U1223, 75015 Paris, France; Université Paris-Sud, Paris-Saclay, 91405 Orsay, France.
4
Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain.
5
Department of Immunology, Weizmann Institute of Science, 76100 Rehovot, Israel.
6
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France.
7
Inserm U1160, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, 75010 Paris, France.
8
Scientific Institute for Research and Health Care "Casa Sollievo della Sofferenza," 71013 San Giovanni Rotondo, Italy.
9
Immunoregulation Unit, Institut Pasteur, 75724 Paris, France.
10
Inserm U1148, Laboratory for Vascular Translational Science (LVTS), CHU X. Bichat, 75877 Paris, France.
11
Université Paris-Diderot, Sorbonne Paris Cité, 75205 Paris, France; Inserm U1152, Faculté de Médicine site Bichat, Université Paris Diderot, Université Sorbonne Paris-Cité, 75018 Paris, France.
12
Inserm U1160, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, 75010 Paris, France; Gastroenterology Department, Hôpital Saint-Louis, AP-HP, 75010 Paris, France.
13
Department of Pulmonary Medicine, Erasmus MC, 3000 CA Rotterdam, Netherlands.
14
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, New York, NY 10065, USA; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France.
15
Inserm U1135, Centre d'Immunologie et des Maladies Infectieuses, 75013 Paris, France.
16
Innate Immunity Unit, Institut Pasteur, 75724 Paris, France; Inserm U1223, 75015 Paris, France. Electronic address: james.di-santo@pasteur.fr.

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.

KEYWORDS:

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

PMID:
28283063
DOI:
10.1016/j.cell.2017.02.021
[Indexed for MEDLINE]
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