title: Systemic Human ILC Precursors Provide a Substrate for Tissue ILC Differentiation.
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.
authors.affiliation: Innate Immunity Unit, Institut Pasteur, 75724 Paris, France; Inserm U1223, 75015 Paris, France; Université Paris-Diderot, Sorbonne Paris Cité, 75205 Paris, France.
authors.forename: Ai Ing
authors.initials: AI
authors.lastname: Lim
authors.affiliation: Innate Immunity Unit, Institut Pasteur, 75724 Paris, France; Inserm U1223, 75015 Paris, France.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Innate Immunity Unit, Institut Pasteur, 75724 Paris, France; Inserm U1223, 75015 Paris, France; Université Paris-Sud, Paris-Saclay, 91405 Orsay, France.
authors.forename: Silvia
authors.initials: S
authors.lastname: Lopez-Lastra
authors.affiliation: Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain.
authors.forename: Ralph
authors.initials: R
authors.lastname: Stadhouders
authors.affiliation: Department of Immunology, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: Franziska
authors.initials: F
authors.lastname: Paul
authors.affiliation: Innate Immunity Unit, Institut Pasteur, 75724 Paris, France; Inserm U1223, 75015 Paris, France.
authors.forename: Armanda
authors.initials: A
authors.lastname: Casrouge
authors.affiliation: Innate Immunity Unit, Institut Pasteur, 75724 Paris, France; Inserm U1223, 75015 Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Serafini
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, 75015 Paris, France; Paris Descartes University, Imagine Institute, 75015 Paris, France.
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.affiliation: Innate Immunity Unit, Institut Pasteur, 75724 Paris, France; Inserm U1223, 75015 Paris, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Surace
authors.affiliation: Innate Immunity Unit, Institut Pasteur, 75724 Paris, France; Inserm U1223, 75015 Paris, France.
authors.forename: Guillemette
authors.initials: G
authors.lastname: Masse-Ranson
authors.affiliation: Department of Immunology, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: David
authors.affiliation: Innate Immunity Unit, Institut Pasteur, 75724 Paris, France; Inserm U1223, 75015 Paris, France.
authors.forename: Helene
authors.initials: H
authors.lastname: Strick-Marchand
authors.affiliation: Inserm U1160, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, 75010 Paris, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Le Bourhis
authors.affiliation: Scientific Institute for Research and Health Care "Casa Sollievo della Sofferenza," 71013 San Giovanni Rotondo, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Cocchi
authors.affiliation: Scientific Institute for Research and Health Care "Casa Sollievo della Sofferenza," 71013 San Giovanni Rotondo, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Topazio
authors.affiliation: Scientific Institute for Research and Health Care "Casa Sollievo della Sofferenza," 71013 San Giovanni Rotondo, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Graziano
authors.affiliation: Scientific Institute for Research and Health Care "Casa Sollievo della Sofferenza," 71013 San Giovanni Rotondo, Italy.
authors.forename: Lucia Anna
authors.initials: LA
authors.lastname: Muscarella
authors.affiliation: Immunoregulation Unit, Institut Pasteur, 75724 Paris, France.
authors.forename: Lars
authors.initials: L
authors.lastname: Rogge
authors.affiliation: Inserm U1148, Laboratory for Vascular Translational Science (LVTS), CHU X. Bichat, 75877 Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Norel
authors.affiliation: 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.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Sallenave
authors.affiliation: Inserm U1160, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, 75010 Paris, France; Gastroenterology Department, Hôpital Saint-Louis, AP-HP, 75010 Paris, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Allez
authors.affiliation: Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain.
authors.forename: Thomas
authors.initials: T
authors.lastname: Graf
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, 3000 CA Rotterdam, Netherlands.
authors.forename: Rudi W
authors.initials: RW
authors.lastname: Hendriks
authors.affiliation: 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.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: Department of Immunology, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: Ido
authors.initials: I
authors.lastname: Amit
authors.affiliation: Inserm U1135, Centre d'Immunologie et des Maladies Infectieuses, 75013 Paris, France.
authors.forename: Hans
authors.initials: H
authors.lastname: Yssel
authors.affiliation: Innate Immunity Unit, Institut Pasteur, 75724 Paris, France; Inserm U1223, 75015 Paris, France. Electronic address: james.di-santo@pasteur.fr.
authors.forename: James P
authors.initials: JP
authors.lastname: Di Santo
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D002454:Cell Differentiation; D019070:Cell Lineage; D005312:Fetal Blood / Q000166:cytology; D005333:Fetus / Q000166:cytology; D006801:Humans; D007113:Immunity, Innate; D020381:Interleukin-17; D008099:Liver / Q000166:cytology; D008168:Lung / Q000166:cytology; D008214:Lymphocytes / Q000166:cytology* / Q000276:immunology; D008221:Lymphoid Tissue / Q000166:cytology; D051379:Mice; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D013234:Stem Cells / Q000166:cytology*; D014158:Transcription, Genetic
chemical_list: D018952:Antigens, CD34; C508717:IL17A protein, human; D020381:Interleukin-17; D019009:Proto-Oncogene Proteins c-kit
keywords: cell fate; cytokines; development; humanized mice; innate lymphoid cells; lymphopoiesis; signaling; single cell cloning; transcription factors