Single-cell RNA-seq identifies a PD-1hi 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 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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Figure 1: scRNA-seq analysis of innate lymphoid progenitors.
Figure 2: PD-1 high expression marks innate lymphoid progenitors.
Figure 3: scRNA-seq dissection of early ILC2 development.
Figure 4: PD-1hi marks effector ILCs.


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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).

Author information




Y.Y. designed research, performed experiments and analysed data. J.C.H.T. performed all of the bioinformatics analyses, C.W. performed experiments. S.C. and C.B. performed influenza infection. J.W. generated the Bcl11btdTomato conditional knockout reporter mice. X.C. performed ChIP–PCR. L.K. did the histologic section staining. L.S.C. analysed the histologic data. L.L. contributed intellectually to the PD-1 experiments. G.T.B. and A.N.J.M. provided Id2GFP and Il13+/tdTomato reporter mice, respectively. S.A.T. and G.D. provided intellectual input for the experiments performed in their laboratories. Y.Y., J.C.H.T. and P. L. wrote the paper. Y. Y. and P. L. conceived the PD-1 as an ILC marker concept. P.L. supervised the research.

Corresponding author

Correspondence to Pentao Liu.

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The authors declare no competing financial interests.

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Nature thanks I. Amit and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data figures and tables

Extended Data Figure 1 Quality control of scRNA-seq data of ILC-progenitor-enriched bone marrow cells.

a, FACS sorting strategies of the adult bone marrow cells from wild-type or Vav-Cre-Bcl11bfl/fl mice. Flt3lo or IL-7Rαlo cells were included to detect more ILC progenitors. LinFlt3lo/−IL-7Rαlo/+α4β7+ cells were further divided into three populations (CD244+CD25, CD244CD25 and CD244CD25+). We sorted two 96-well plates of CD244+CD25, one plate of CD244CD25 and one plate of ILC2 progenitors CD244CD25+ to include most ILC progenitors for scRNA-seq. Two 96-well plates of LinFlt3IL-7Rα+α4β7+ bone marrow cells from Vav-Cre-Bcl11bfl/fl mice were purified to investigate early ILC2 development defects. Lin: CD19, CD3, CD4, CD5, CD8, TCRβ, TCRγδ, NK1.1, CD11b, Gr-1, CD11c and Ter119. b, Column charts show the fraction of cells passing specific quality control criteria in each plate: unique count mapped to annotated genes >500,000 (top panel); count mapped to mitochondrial-encoded genes <10% (middle panel); and number of annotated gene detected >2,500 (bottom panel). c, Percentage of cells passing all criteria. d, The percentages of ERCC RNA spike-ins in each plate. The black dots represent the mean of the dataset. e, The total number of unique counts mapped to annotated genes in different plates. The black dots represent the mean of the dataset. f, The fractions of the 92 external ERCC RNA spike-ins in different plates. g, Kolmogorov–Smirnov test of individual ERCC spike-ins between the two plates did not detect any ERCC spike-ins showing significantly different (log2 fold change > 1, and adjusted P value < 0.05) levels. The two vertical lines mark the log2 fold change levels of −1 and 1, the horizontal line marks the adjusted P value threshold of 0.05. h, Identification of highly variable genes. Brown points represent annotated mouse genes. Blue points represent external ERCC RNA spike-ins. The magenta points represent the mouse genes that show significantly higher variability (false discovery rate < 0.1). The solid line represents the fit of the technical noise, the dashed line represents the 50% biological CV (coefficient of variation). i, Biaxial t-SNE clustering of the sequenced wild-type cells. j, Column chart comparing the percentage of cells which show detectable mRNA expression of lineage markers in the wild-type bone marrow cells.

Extended Data Figure 2 t-SNE plots showing expression and distribution of genes described in the manuscript.

The colour key shows the expression level.

Extended Data Figure 3 Violin plots of genes highly enriched in specific clusters.

The y axis indicates the log2 (normalized count + 1) expression levels. The black point indicates the mean of expression level. The x axis indicates different clusters.

Extended Data Figure 4 Heat map of TCR transcripts in different cell clusters.

Extended Data Figure 5 PD-1hi expression marks ILC progenitors.

a, Correlation of expression levels of Pdcd1 and Zbtb16 in C6 cells. Correlation was calculated by Pearson’s method. The fit represents the line of linear regression. b, Violin plot showing the selected gene expression in PD-1hi cells of C6. The y axis indicates the log2 (normalized count + 1) expression levels. The black point indicates the mean of expression level. c, Expression of ILC markers in PD-1hi cells was analysed by FACS. d, The in vivo developmental potential of PD-1hi cells. CD45.1 Rag2−/−Il2rg−/− recipients were injected with the equal numbers of CD45.1CD45.2+ PD-1hi cells and CD45.1+CD45.2+ (F1 of CD45.1 and CD45.2 parents) common lymphoid progenitors (200–800 cells). The progenies of these donor cells were analysed by FACS after 5–7 weeks (n = 3 per donor cell type). e, Clonal analysis of PD-1hi cells in vitro. The PD-1hi, PD-1hiBcl11b+ and PD-1hiBcl11b bone marrow cells were FACS-purified and cultured on stromal cells and analysed by FACS. ILC1 was defined as CD45+NK1.1+Bcl11b, ILC2 as CD45+NK1.1Bcl11b+ and ILC3 as CD45+NK1.1Bcl11bRORγt+. Data are representatives of two (c) or three (d) independent experiments.

Extended Data Figure 6 Direct comparison of PD-1hi and PLZFhi ILC progenitors and dissection of the heterogeneity in the ILC progenitor compartments.

a, FACS plots show PLZFhi and PD-1hi cells had the same development potential in vivo. The equal numbers of PD-1hi cells and PLZFhi cells were adoptively transferred into the same recipient and analysed 3–4 weeks later (n = 3 per donor cell type). b, Schematic diagram of the Bcl11btdTomato conditional knockout reporter allele, where the loxP-IRES-tdTomato cassette was inserted to the 3′UTR of the Bcl11b locus. The other loxP site was in intron 3. Cre-loxP recombination would delete the exon 4. The selection cassette for initial gene targeting was excised by Flpase-FRT recombination. c, Expression of Bcl11b in CHILPs were analysed in the Id2GFP;Bcl11btdTomato duel reporter mice (n = 6). d, Expression of Bcl11b in PD-1hi bone marrow cells was analysed by FACS (n = 6). e, FACS analysis of the in vivo developmental potential of PD-1hiBcl11b cells (n = 3 per donor cell type). Common lymphoid progenitors were used as the donor cell control. PD-1hiBcl11b cells predominantly generated ILC1, ILC2 and ILC3. Data are representatives of two (a, e) or three (c, d) independent experiments.

Extended Data Figure 7 scRNA-seq analysis of PD-1hi bone marrow cells.

a, t-SNE clustering analysis of sequenced PD-1hi cells detected two subpopulations. b, Heat map showing the hierarchical clustering result of PD-1hi cells based on selected ILC regulators. The expression levels are log2 transformed and ERCC-size factor normalized.

Extended Data Figure 8 scRNA-seq dissection of early ILC2 development.

a, Analysis of scRNA-seq data identified genes showing expression changes in C6, C7a, C8 and C9 cells. Change and distribution of expression of selected genes are shown. Il17rb and Bcl11b are among the genes showing spike expression from C6 to C9, whereas Il1rl1 (IL-33R) showed steadily increased expression. The bottom t-SNE plots showing expression of representative genes. b, The expression of IL-25R in PD-1hi bone marrow cells in the Bcl11btdTomato mice (n = 3). c, Clonal differentiation assay of PD-1hiIL-25R+ and PD-1hiIL-25R cells. Cells were cultured on OP9-DL1 stromal cells in the presence of IL-7 (20.0 ng ml−1) and SCF (50.0 ng ml−1) and were analysed 10 days later. ILC1 was defined as CD45+NK1.1+Bcl11b, ILC2 as CD45+NK1.1Bcl11b+ and ILC3 as CD45+NK1.1Bcl11bRORγt+. d, FACS analysis of the in vivo developmental potential of PD-1hiIL-25R+ cells. CD45.1 Rag2−/−Il2rg−/− recipients were injected with equal numbers of CD45.1CD45.2+ PD-1hiIL-25R+ cells and CD45.1+CD45.2+ common lymphoid progenitors (100–500 of each) and the progenies of these populations were analysed 5–7 weeks later (n = 5 per group). e, Analysis of ILCs in Vav-Cre-Bcl11bfl/fl mice. LinIL-33R+IL-7Rα+ ILC2s, LinKLRG1+IL-7Rαlo ILC2 or LinNK1.1+NKp46+ ILCs from the bone marrow, lung or siLP were analysed (n = 4 per genotype), respectively. f, ‘Natural’ ILC2 (nILC2), ‘inflammatory’ ILC2 (iILC2) and BALF IL-5 were analysed in Vav-Cre-Bcl11bfl/fl and the control mice after administration of IL-25 (200 ng per mouse per day) for 3 consecutive days (n = 5 per treated group). Error bars denote s.e.m. g, FACS analysis of in vivo developmental potential of PD-1hi cells from Vav-Cre-Bcl11bfl/fl mice. CD45.1 Rag2−/−Il2rg−/− mice were injected with CD45.2 PD-1hi cells sorted from Bcl11bfl/fl or Vav-Cre-Bcl11bfl/fl mice. The progenies of these donor cells were analysed 4–7 weeks later by FACS (n = 3 per genotype). Data are representatives of three (b) or two (dg) independent experiments. *P < 0.05, **P < 0.01 (two-tailed t-test).

Extended Data Figure 9 Restoration of development of Bcl11b-deficient PD-1hi ILC progenitors to ILC2 by overexpressing IL-25R.

a, FACS plots showing the expression of TCF-1 and Gata3 in mutant PD-1hi bone marrow cells. Protein expression was measured by intracellular antibody staining. b, Expression patterns of Tox, Id2, Tcf7 and Gata3 in the sequenced Bcl11b-deficient bone marrow cells. c, Overexpressing Il17rb in Bcl11b-deficient PD-1hi bone marrow cells. The rescued cells were analysed by FACS for ILC2 surface markers. PD-1hi cells sorted from Vav-Cre-Bcl11bfl/fl mice were transduced with the Il17rb or control retrovirus. The infected cells were cultured on OP9-DL1 stromal cells with the helper CD45.1 ILC2 progenitors in the presence of IL-25 (20.0 ng ml−1), IL-7 (20.0 ng ml−1) and SCF (50.0 ng ml−1). The cells were collected and analysed after two weeks of culture. Data are representatives of two (a, c) independent experiments.

Extended Data Figure 10 PD-1hi marks effector ILCs.

a, FACS analysis of PD-1 expression on peripheral ILCs in steady-state mice (n = 3). b, Gating strategies of lung ILCs. Lung cNK cells were gated as LinId2+IL-7RαNK1.1+NKp46+; lung ILC1s as LinId2+IL-7Rα+NK1.1+Bcl11b; lung ILC2s as LinId2+IL-7Rα+NK1.1Bcl11b+; and lung ILC3s as LinId2+IL-7Rα+NK1.1Bcl11b. The data were from influenza-infected mice at 5 days after infection. cNKs count for at least half of the Lin leukocytes in these mice (n = 3). c, FACS analysis of PD-1 expression on CD3+ T cells, CD19+ B cells and peripheral ILCs after J43 treatment (n = 3). The tissues were collected at day 14 after J43 treatment. d, FACS plot shows the recognition of different epitopes of PD-1 by PD-1 antibody clones RMP1-30 and J43. The majority of lung PD-1hi ILC2s were stained with both RMP1-30 and J43. e, FACS analysis of lung PD-1hi cNK, ILC1 and ILC3 at 7 days after infection (n = 3). f, BALF cytokines were quantitated as shown (n = 3 per group per time point). The four experimental groups were: Rag1−/− mice with mock infection; Rag1−/− mice infected with A/X-31 and treated with either an antibody isotype control or J43; Rag2−/−Il2rg−/− mice infected with A/X-31 as the ILC-deficient control. g, More PD-1hi cells were found after papain challenge (day 6) in Rag1−/− mice (n = 3). h, Rag1−/− mice were pretreated with PD-1 antibody J43 or the isotype control antibody for 3 days and then administrated with papain (intranasally) for 5 consecutive days. The lung tissue was collected at day 6 for analysis (n = 5 per treatment). Lung ILC2s were reduced in J43 treated mice. PD-1hi and IL-5-producing ILC2 were undetectable after J43 administration. Data are representatives of two (ah) independent experiments. Error bars (f, h) denote s.e.m. *P < 0.05, **P < 0.01 (two-tailed t-test).

Supplementary information

Supplementary Table 1

This file contains clustering information of bone marrow progenitors. (XLSX 38 kb)

Supplementary Table 2

This file contains clustering information of PD-1hi cells. (XLSX 17 kb)

Supplementary Table 3

This file contains differential gene analysis of WT C6 vs C8. (XLSX 2880 kb)

Supplementary Table 4

This file contains ILC gene set in GESA (XLSX 21 kb)

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Yu, Y., Tsang, J., Wang, C. et al. Single-cell RNA-seq identifies a PD-1hi ILC progenitor and defines its development pathway. Nature 539, 102–106 (2016).

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