title: Single-cell RNA-seq identifies a PD-1hiILC progenitor and defines its development pathway.
abstract: Innate lymphoid cells (ILCs) functionally resemble T lymphocytes in cytotoxicity and cytokine production but lack antigen-specific receptors, and they are important regulators of immune responses and tissue homeostasis. ILCs are generated from common lymphoid progenitors, which are subsequently committed to innate lymphoid lineages in the α-lymphoid progenitor, early innate lymphoid progenitor, common helper innate lymphoid progenitor and innate lymphoid cell progenitor compartments. ILCs consist of conventional natural killer cells and helper-like cells (ILC1, ILC2 and ILC3). Despite recent advances, the cellular heterogeneity, developmental trajectory and signalling dependence of ILC progenitors are not fully understood. Here, using single-cell RNA-sequencing (scRNA-seq) of mouse bone marrow progenitors, we reveal ILC precursor subsets, delineate distinct ILC development stages and pathways, and report that high expression of programmed death 1 (PD-1hi) marked a committed ILC progenitor that was essentially identical to an innate lymphoid cell progenitor. Our data defined PD-1hiIL-25Rhias an early checkpoint in ILC2 development, which was abolished by deficiency in the zinc-finger protein Bcl11b but restored by IL-25R overexpression. Similar to T lymphocytes, PD-1 was upregulated on activated ILCs. Administration of a PD-1 antibody depleted PD-1hiILCs and reduced cytokine levels in an influenza infection model in mice, and blocked papain-induced acute lung inflammation. These results provide a perspective for exploring PD-1 and its ligand (PD-L1) in immunotherapy, and allow effective manipulation of the immune system for disease prevention and therapy.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.|Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China.|Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
authors.forename: Jason C H
authors.initials: JC
authors.lastname: Tsang
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.|Institute of Animal Husbandry and Veterinary Science, Shanghai Academy of Agricultural Sciences, Shanghai 201106, China.
authors.forename: Cui
authors.initials: C
authors.lastname: Wang
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Clare
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Juexuan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Cordelia
authors.initials: C
authors.lastname: Brandt
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Leanne
authors.initials: L
authors.lastname: Kane
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Lia S
authors.initials: LS
authors.lastname: Campos
authors.affiliation: Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Lu
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Gabrielle T
authors.initials: GT
authors.lastname: Belz
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors.forename: Andrew N J
authors.initials: AN
authors.lastname: McKenzie
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.|European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Teichmann
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.|Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0SP, UK.
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.
authors.forename: Pentao
authors.initials: P
authors.lastname: Liu
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D001483:Base Sequence; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics; D002469:Cell Separation; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate; D007167:Immunotherapy / Q000639:trends; D007251:Influenza, Human / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D054503:Lymphoid Progenitor Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000378:metabolism; D012097:Repressor Proteins / Q000172:deficiency / Q000378:metabolism; D059010:Single-Cell Analysis; D013601:T-Lymphocytes / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism
chemical_list: D000906:Antibodies; C511143:Bcl11b protein, mouse; D016207:Cytokines; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D018123:Receptors, Interleukin; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins