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

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 homeostasis1,2. ILCs are generated from common lymphoid progenitors, which are subsequently c...

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Published in:Nature (London) 2016-11, Vol.539 (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: Article
Language:English
Subjects:
Bone marrow
Cellular biology
Cytokines
Cytotoxicity
Heterogeneity
Immune system
Immunotherapy
Infections
Inflammation
Ligands
Lymphocytes
Ribonucleic acid
RNA
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Summary: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 homeostasis1,2. ILCs are generated from common lymphoid progenitors, which are subsequently committed to innate lymphoid lineages in the a-lymphoid progenitor, early innate lymphoid progenitor, common helper innate lymphoid progenitor and innate lymphoid cell progenitor compartments3-8. ILCs consist of conventional natural killer cells and helper-like cells (ILC1, ILC2 and ILC3)9. Despite recent advances1,2,10, 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-1hl) marked a committed ILC progenitor that was essentially identical to an innate lymphoid cell progenitor. Our data defined PD-1hiIL-25Rhi 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-1hi 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.
ISSN:0028-0836
1476-4687
DOI:10.1038/nature2OlO5