Single-cell RNA-seq identifies a PD-1 hi ILC progenitor and defines its development pathway

• Published in: Nature (London) Vol. 539; no. 7627; p. 102
• Main Authors: Yu, Yong, Tsang, Jason C H, Wang, Cui, Clare, Simon, Wang, Juexuan, Chen, Xi, Brandt, Cordelia, Kane, Leanne, Campos, Lia S, Lu, Liming, Belz, Gabrielle T, McKenzie, Andrew N J, Teichmann, Sarah A, Dougan, Gordon, Liu, Pentao
• Format: Journal Article
• Language: English
• Published: England 03.11.2016
• Subjects: Animals; Antibodies - immunology; Base Sequence; Cell Differentiation; Cell Lineage - genetics; Cell Separation; Cytokines - immunology; Cytokines - metabolism; Disease Models, Animal; Humans; Immunity, Innate; Immunotherapy - trends; Influenza, Human - immunology; Influenza, Human - metabolism; Killer Cells, Natural - cytology; Lymphocyte Activation; Lymphocytes - cytology; Lymphocytes - immunology; Lymphocytes - metabolism; Lymphoid Progenitor Cells - cytology; Lymphoid Progenitor Cells - metabolism; Mice; Mice, Inbred C57BL; Pneumonia - immunology; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - immunology; Programmed Cell Death 1 Receptor - metabolism; Receptors, Interleukin - metabolism; Repressor Proteins - deficiency; Repressor Proteins - metabolism; Single-Cell Analysis; T-Lymphocytes - metabolism; Tumor Suppressor Proteins - deficiency; Tumor Suppressor Proteins - metabolism
• ISSN: 1476-4687

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-1 ) marked a committed ILC progenitor that was essentially identical to an innate lymphoid cell progenitor. Our data defined PD-1 IL-25R as 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-1 ILCs 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.