title: IL-12 drives functional plasticity of human group 2 innate lymphoid cells.
abstract: Group 2 innate lymphoid cells (ILC2) include IL-5- and IL-13-producing CRTh2(+)CD127(+)cells that are implicated in early protective immunity at mucosal surfaces. Whereas functional plasticity has been demonstrated for both human and mouse ILC3 subsets that can reversibly give rise to IFN-γ-producing ILC1, plasticity of human or mouse ILC2 has not been shown. Here, we analyze the phenotypic and functional heterogeneity of human peripheral blood ILC2. Although subsets of human CRTh2(+)ILC2 differentially express CD117 (c-kit receptor), some ILC2 surface phenotypes are unstable and can be modulated in vitro. Surprisingly, human IL-13(+)ILC2 can acquire the capacity to produce IFN-γ, thereby generating plastic ILC2. ILC2 cultures demonstrated that IFN-γ(+)ILC2 clones could be derived and were stably associated with increased T-BET expression. The inductive mechanism for ILC2 plasticity was mapped to the IL-12-IL-12R signaling pathway and was confirmed through analysis of patients with Mendelian susceptibility to mycobacterial disease due to IL-12Rβ1 deficiencies that failed to generate plastic ILC2. We also detected IL-13(+)IFN-γ(+)ILC2 ex vivo in intestinal samples from Crohn's disease patients. These results demonstrate cytokine production plasticity for human ILC2 and further suggest that environmental cues can dictate ILC phenotype and function for these tissue-resident innate effector cells.
authors.affiliation: Innate Immunity Unit, Institut Pasteur, 75724 Paris, France Institut National de la Santé et de la Recherche Médicale (INSERM) U1223, 75015 Paris, France.
authors.forename: Ai Ing
authors.initials: AI
authors.lastname: Lim
authors.affiliation: Immunoregulation Unit, Institut Pasteur, 75724 Paris, France.
authors.forename: Silvia
authors.initials: S
authors.lastname: Menegatti
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France Paris Descartes University, Imagine Institute, 75015 Paris, France Center for the Study of Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker-Enfants Malades Hospital, 75015 Paris, France St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
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: INSERM U1160, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, 75010 Paris, France Gastroenterology Department, Hôpital Saint-Louis, AP-HP Paris, 75010 Paris, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Allez
authors.affiliation: Immunoregulation Unit, Institut Pasteur, 75724 Paris, France.
authors.forename: Lars
authors.initials: L
authors.lastname: Rogge
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 Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065 Pediatric Hematology-Immunology Unit, Necker-Enfants Malades Hospital, 75015 Paris, France.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
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 Institut National de la Santé et de la Recherche Médicale (INSERM) U1223, 75015 Paris, France james.di-santo@pasteur.fr.
authors.forename: James P
authors.initials: JP
authors.lastname: Di Santo
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003424:Crohn Disease / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology*; D018793:Interleukin-13 / Q000276:immunology; D015848:Interleukin-5 / Q000276:immunology; D007422:Intestines / Q000276:immunology* / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice
chemical_list: C573415:IFNG protein, human; C578095:IL13 protein, human; C508599:IL5 protein, human; D018793:Interleukin-13; D015848:Interleukin-5; D018664:Interleukin-12; D007371:Interferon-gamma