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

Ai Ing Li (1, 2) , Yan Li (2) , Silvia Lopez-Lastra (3, 2) , Ralph Stadhouders (4) , Franziska Paul (5) , Armanda Casrouge (2) , Nicolas Serafini (2) , Anne Puel (6) , Jacinta Bustamante (6) , Laura Surace (2) , Guillemette Masse-Ranson (2) , Eyal David (5) , Helene Strick-Marchand (2) , Lionel Le Bourhis (7) , Roberto Cocchi (8) , Davide Topazio (8) , Paolo Graziano (8) , Lucia Anna Muscarella (8) , Lars Rogge (9) , Xavier Norel (10) , Jean-Michel Sallenave (1) , Matthieu Allez (11, 7) , Thomas Graf (4) , Rudi W Hendriks (12) , Jean-Laurent Casanova (13, 6, 14, 15) , Ido Amit (5) , Hans Yssel (16) , James P Di Santo (17)

1 UPD7 - Université Paris Diderot - Paris 7
2 Immunité Innée - Innate Immunity
3 UP11 - Université Paris-Sud - Paris 11
4 BIST - Barcelona Institute of Science and Technology
5 Weizmann Institute of Science [Rehovot, Israël]
6 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
7 IUH - Institut Universitaire d'Hématologie
8 IRCCS - Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo]
9 Immunorégulation
10 LVTS (UMR_S_1148 / U1148) - Laboratoire de Recherche Vasculaire Translationnelle
11 Hôpital Saint-Louis
12 Erasmus MC - Erasmus University Medical Center [Rotterdam]
13 CHU Necker - Enfants Malades [AP-HP]
14 St. Giles Laboratory of Human Genetics of Infectious Diseases
15 HHMI - Howard Hughes Medical Institute
16 CIMI - Centre d'Immunologie et de Maladies Infectieuses
17 IP - Institut Pasteur [Paris]

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

Domains: Immunology

Ai Ing Li, Yan Li, Silvia Lopez-Lastra, Ralph Stadhouders, Franziska Paul, et al.. Systemic Human ILC Precursors Provide a Substrate for Tissue ILC Differentiation.. Cell, 2017, 168 (6), pp.1086-1100.e10. ⟨10.1016/j.cell.2017.02.021⟩. ⟨pasteur-01501939⟩