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 α-lymphoid progenitor, early innate lymphoid progenitor, common helper innate lymphoid progenitor and innate lymphoid cell progenitor compartments3,4,5,6,7,8. 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-1hi) 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.
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We thank F. Colucci and J. Di Santo for providing Rag2−/−Il2rg−/− mice. We thank the Sanger Institute RSF (J. Bussell, D. Key, A. Kirton, L. Bulman, S. Kemp, P. Green, P. Zielezinski, R. Lacey, C. Rogerson, A. Logan and G. Notley), Flow Cytometry Core Facility (B. L. Ng, J. Graham and C. Hall), Single Cell Genomic Core Facility (S. Loren and I. Bronner) and DNA sequencing pipeline (N. Smerdon) for technical assistances. We thank K. Chen, J. Pramanik and R. Miragaia for technical help. C.W. is supported by the Plan of Youth Growth from Shanghai Municipal Agricultural Committee (Hunongqingzi (2015. No. A-35)). L.L. is funded by National Natural Science Foundation of China (31370904, 81671579). G.T.B. is supported by the Australian Research Council (Future Fellowship FT110100283) and the National Health and Medical Research Council (Fellowship 10402092). A.N.J.M. is supported by the Medical Research Council (U105178805) and Wellcome Trust (100963/Z/13/Z). This work is supported by Wellcome Trust (grant number 098051) (P.L).
Extended data figures
This file contains clustering information of bone marrow progenitors.
This file contains clustering information of PD-1hi cells.
This file contains differential gene analysis of WT C6 vs C8.
This file contains ILC gene set in GESA