Abstract
Innate lymphoid cells (ILCs) play important functions in immunity and tissue homeostasis, but their development is poorly understood. Through the use of single-cell approaches, we examined the transcriptional and functional heterogeneity of ILC progenitors, and studied the precursor–product relationships that link the subsets identified. This analysis identified two successive stages of ILC development within T cell factor 1-positive (TCF-1+) early innate lymphoid progenitors (EILPs), which we named ‘specified EILPs’ and ‘committed EILPs’. Specified EILPs generated dendritic cells, whereas this potential was greatly decreased in committed EILPs. TCF-1 was dispensable for the generation of specified EILPs, but required for the generation of committed EILPs. TCF-1 used a pre-existing regulatory landscape established in upstream lymphoid precursors to bind chromatin in EILPs. Our results provide insight into the mechanisms by which TCF-1 promotes developmental progression of ILC precursors, while constraining their dendritic cell lineage potential and enforcing commitment to ILC fate.
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Acknowledgements
We thank H.-R. Rodewald for sharing Il7r-iCre mice and J. Richa from the Transgenic and Chimeric Mouse Facility, University of Pennsylvania, for injection of Tcf7YFP embryonic stem cells into mouse blastocysts. We thank T. Ciucci, R. Bosselut, J. Chen, the CCR Sequencing Facility, the CCR Flow Cytometry Core Facility, and the DNA Sequencing Facility of the University of Pennsylvania for technical support. This work utilized the computational resources of the NIH high-performance computing Biowulf cluster (http://hpc.nih.gov). This research was supported by the Intramural Research Program of the NIH, National Cancer Institute and Center for Cancer Research, and by grants from the NIH (AI121080 and AI139874 to H.-H.X.), Veteran Affairs BLR&D Merit Review Program (BX002903A to H.-H.X.), and Foundation pour la Recherche Médicale (DEQ20170839118 to C.H.) and National Research Agency Investissements d’Avenir via the program LabEX IGO (ANR-11-LABX-0016-01 to C.H.).
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C.H. designed the research and performed most of the experiments, alongside D.K. and G.R. C.H., B.L., M.C.C. and A.B. analyzed the data. C.H., M.C.C., T.R. and A.B. produced the figures. C.H., T.R., Q.Y. and H.-H.X. designed and generated the new mouse models. C.H., K.Z. and A.B. directed and oversaw the experiments. C.H. and A.B. wrote the paper. All authors helped to design the research, and read and commented on the manuscript.
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Supplementary Figure 1 Representative gating strategy used for flow cytometric analysis.
(a) Single cell suspensions made from bone marrow are depleted of RBCs using osmotic lysis, then depleted for LinILC+ cells (see Methods), stained using DAPI, and analyzed by flow cytometry. (b) For visualization of ILC precursors, an additional LinILC- Kit+ gate is applied before gating shown in Fig. 1a.
Supplementary Figure 2 Differentiation potential of EILPs in vitro.
Flow cytometric analysis of cultures from single EILPs sorted into 96 well plates and cultured for 10 days in either SF7-GM3 or SF7-GM3-MG6 conditions. (a-b) Examples of single EILP-derived colonies showing the lineages identified. Arrows show successive gating. Numbers indicate the percentage of cells in each gate. (c) Composition of the ILC+ wells. Each column represents one well, positive wells are indicated in black for individual lineage. (d) Quantification of absolute numbers of Mac-1+ cells per Mac-1+ colony in SF7-GM3 condition (n=50 colonies) and SF7-GM3-MG6 condition (n=191 colonies). Data are presented as mean + SD. A two-tailed unpaired Student’s t-test was performed to determine significance, and showed that difference is not significant. (e) Representative profile of Mac-1+ colonies gated on Mac-1+ cells. (f) Percentage of Mac-1+ wells containing cDC1, cDC2, or both lineages as shown in e. All data are representative of three independent experiments.
Supplementary Figure 3 Generation of a Tcf7YFP reporter mouse.
(a) Strategy for the generation of a Tcf7YFP allele by insertion of a P2A-YFP sequence downstream of the Tcf7 C-terminus, followed by deletion of the floxed neo cassette using a CMV-Cre mouse strain. The P2A ribosomal skipping peptide allows bicistronic generation of separate Tcf7 and YFP molecules, but both driven by the Tcf7 promoter at equimolar amounts. Tcf7 exons are numbered (E3-E9), and the scale and the location of the MfeI restriction sites and Southern blot probe used to screen the targeted ES clones are indicated. (b) Identification by Southern blot of an ES clone with the expected homologous recombination (+/-) compared to a wild-type clone (-/-). Genomic DNA was extracted, digested with MfeI, and blotted with the probe shown in a. (c) Flow cytometric analysis of LinILC- Kit+ CD122low α4β7+ BM cells of the indicated mouse strains. Data are representative of three independent experiments.
Supplementary Figure 4 Characterization of EILP subsets.
(a) RNA-seq analysis of ALPs, sEILPs, cEILPs and ILCPs. Hierarchical clustering using complete linkage calculated from Euclidian distances. (b-c) Flow cytometric analysis of cultures from single sEILPs and cEILPs sorted into 96 well plates and cultured for 10 days in either SF7-GM3 or SF7-GM3-MG6 conditions. Data are pooled from 2 out of 3 representative experiments. (b) Frequency of wells containing ILC progenitors as shown in Supplementary Fig. 2a, in SF7-GM3 condition. Data are presented as % of ILC positive wells ± SEP for n=78 sEILP wells and n=143 cEILP wells. (c) Frequency of ILC positive colonies containing the indicated combination of mature ILCs, identified as shown in Supplementary Fig. 2a. (d) Flow cytometric analysis of sEILPs and cEILPs. (e) Flow cytometric analysis of intracellular DAPI staining on sEILPs and cEILPs. (f) Flow cytometric analysis of cultures from sEILPs after two days in SF7 condition. Based on Mac-1, TCF-1, Thy1, and PLZF expression (left), the derived populations were separated into DC (Mac-1+, grey), sEILP (TCF-1+ PLZF- Thy1-, black), cEILP (TCF-1+ PLZF+ Thy1-, orange), and ILCP (TCF-1+ PLZF+ Thy1+, purple), and analyzed for expression of transcription factors (right). Arrows show successive gating. (g-h) Flow cytometric analysis of sEILP1s (green), sEILP2s (blue), cEILPs (orange) and pre-DCs (grey) in Tcf7YFP mice (g) or wild-type mice (h). (i) Flow cytometric analysis of cultures from Tcf7-YFP+ sEILP1s and sEILP2s after two days in SF7 condition, gated on Tcf7-YFP- cells. (j-k) Flow cytometric analysis of cultures from single sEILP1 and sEILP2 cells sorted into 96 well plates after 10 days in SF7-GM3 or SF7-GM3-MG6 conditions. (j) Quantification of wells containing cDC1s, cDC2s, or both lineages as defined in Supplementary Fig. 2e. (k) Quantification of absolute numbers of DCs per DC positive colony in n=159 colonies derived from sEILP1s and n=6 colonies derived from sEILP2s. Data are presented as mean + SD. A two-tailed unpaired Student’s t-test with Welsh correction was performed to determine significance. ***p<0.005. (e,f,i) Numbers indicate the percentage of cells in each gate. All data are representative of three independent experiments.
Supplementary Figure 5 DC potential of EILPs in vivo.
(a-b) Flow cytometric analysis of BM cells from wild-type mouse defining the indicated populations. Arrows show successive gating. (c) Flow cytometric analysis of pre-DCs defined in a (grey), pre-cDC1s defined in b (blue), sEILPs (black) and CD11c+ EILPs defined in Fig. 4d (red). (d) Flow cytometric analysis of the indicated BM precursors (black) compared to Lin Kit BM cells (grey). (e) Flow cytometric analysis of Il7r-Cre R26-stop-YFP Tcf7EGFP/+ DC subsets defined in b. (a-e) Data are representative of three independent experiments. (f) Flow cytometric analysis of BM cells from CD45.1+ mice that were lethally irradiated (850 rads), injected with Tox-/- or wild-type littermate CD45.2+LinILC-KithighSca-1+ BM cells mixed with CD45.1+LinILC-KithighSca-1+ BM cells, and reconstituted for 10–12 weeks. Profiles of LinILC-KithighSca-1+ cells and granulocytes from BM, and cDC1s (CD8α+Mac-1lo) and cDC2s (CD8α-Mac-1hi) from spleen are shown. Data are pooled from two independent experiments that gave similar results, and presented as mean ± SEM for n=7 mice per group. A two-tailed unpaired Student’s t-test was performed to determine significance. ns, not significant. (a,b,e,f) Numbers indicate the percentage of cells in each gate.
Supplementary Figure 6 Generation of a Tcf7EGFPnull mouse and analysis of EILPs in Tcf7null mice.
(a) Strategy of generation of a Tcf7EGFPnull allele by breeding the Tcf7EGFP mouse with the CMV-Cre mouse strain. (b) Flow cytometric analysis of CD3ε+ splenocytes from Tcf7-/- (grey shaded histogram), Tcf7EGFP/+ (black histogram), and Tcf7EGFPnull/- (red histogram) mice for GFP expression on unfixed samples, or TCF-1 expression detected by intracellular staining with antibodies targeting either the N-terminal (C63D9) or C-terminal (C46C7) domains of TCF-1. (c) Flow cytometric analysis of thymus from mice of the indicated genotype. (d) Numbers of thymocytes for Tcf7-/- (n=4), Tcf7EGFP/+ (n=6), and Tcf7EGFPnull/- (n=6) mice pooled from three independent experiments. Data are presented as mean ± SEM. (e) Flow cytometric analysis of LinILC- Kit+ CD122low BM cells from Tcf7EGFPnull/+ and Tcf7EGFPnull/- littermate mice. (f) Flow cytometric analysis of EILPs from e. (g) Flow cytometric analysis of LinILC-depleted BM cells from mice of the indicated genotype. Arrows show successive gating. (h) Flow cytometric analysis and quantification of LinILC- Kit+ BM cells of Tcf7EGFPnull/+ and Tcf7EGFPnull/- littermate mouse. Data are presented as mean ± SEM for n=3 mice per group. (c,e,g) Numbers indicate the percentage of cells in each gate. (d,h) A two-tailed unpaired Student’s t-test was performed to determine significance. ns, not significant; **p<0.01, ***p<0.005. (b-c,e-h) Data are representative of three independent experiments. (i) RNA-seq analysis averaged from 3 ALP samples, 2 Tcf7EGFPnull/- EILP samples, and 2 Tcf7EGFPnull/+ sEILP samples. Significance was calculated using a linear model (anova), applying the empirical Bayes method for estimating variance. Volcano plots show significantly upregulated or downregulated genes by more than two-fold from ALPs to wild-type sEILPs colored in red and green respectively.
Supplementary Figure 7 TCF-1 mechanism of action.
(a,b) Flow cytometric analysis of cultures from single sEILP sorted from Tcf7EGFPnull/+ and Tcf7EGFPnull/- littermate mice into 96 well plates, after 10 days in SF7-GM3 or SF7-GM3-MG6 conditions. (a) Quantification of wells containing ILCs, DCs, or both lineages. (b) Quantification of absolute numbers of Mac-1+ DCs per DC positive colony. Data are pooled from both cytokine conditions and presented as mean + SD. Statistics are calculated using n=12 DC positive colonies derived from Tcf7EGFPnull/+ sEILPs and n=34 DC positive colonies derived from Tcf7EGFPnull/- sEILPs. A two-tailed unpaired Student’s t-test with Welsh correction was performed to determine significance. **p<0.01. (c-e) scRNA-seq analysis of Tcf7-GFP+ BM progenitors isolated from Tcf7EGFPnull/- mice and compared to wild-type ALPs and Tcf7-GFP+ BM progenitors. (c) t-SNE plots showing pseudo-time ordering scores of individual ALP (n=786 cells), Tcf7-GFP+ Tcf7EGFP/+ cells (n=1799) and Tcf7-GFP+ Tcf7EGFPnull/- cells (n=594) shown in Fig. 6b along the two progressions from Fig. 1e. The ordering score of individual cells is represented in colors going from light grey to violet for a given progression. Cells that are not part of the progression are dark grey. (d) Quantification of TCF-1 deficient and sufficient sEILP1s in each progression from b, calculated as percentage of sEILP1. The size of the circle is relative to the percentage of cells. (e) Expression of the indicated genes of individual TCF-1 deficient (black) and sufficient (pink) sEILP1s in each progression (main or alt. for alternative) as shown in c and d. Statistics are calculated on n=224 main sEILP1s and n=75 alt. sEILP1s that are TCF-1 deficient, and n=585 main sEILP1s and n=84 alt. sEILP1s that are TCF-1 sufficient. (f) LEAP analysis modelling the transcriptional network underlying ILC development. Interactions between transcription factors. Only interactions with the 10 most connected controllers are represented. Controllers downregulated during ILC development are shown in green, controllers upregulated are in red. The size of each controller is proportional to its network connectivity. See Supplementary Table 6 for the whole network. (g) TCF-1 ChIC-seq analysis in EILPs and DNase-seq analysis in ALPs, EILPs, ILCPs. Heat map centered on TCF-1 binding sites in EILPs (± 2kb) that are not located in region of DNase I hypersensitivity in ALPs (left), and quantification of DNase I hypersensitivity enrichment (right). (h) scRNA-seq analysis as in c-e. Expression of the indicated genes of individual TCF-1 deficient (n=224, black) and sufficient (n=585, pink) sEILP1s from the Main developmental progression as shown in c and d. (e,h) A two-sided Wilcoxon rank-sum test was used to determine the significance of gene expression differences between TCF-1 deficient and sufficient cells for a given subset. **p<0.01, ***p<0.005. See also Supplementary Table 4. (i) Scheme of early ILC development showing the progenitor-successor relationships between EILP subsets, and their developmental fate. The transcription factors required for the described developmental progression are indicated.
Supplementary information
Supplementary Information
Supplementary Figs. 1–7
Supplementary Table 1: Genes dynamically expressed during wild-type ILC development in scRNA-Seq
Cell clusters separated by pseudotime were compared with each other. Clusters as defined in Fig. 1c are compared along the main (ALP (n = 752), sEILP1 (n = 585), cEILP (n = 409), ILCP (n = 414), ILC2P (n = 111)) or alternative pseudotimes (ALP (n = 751), sEILP1 (n = 84), sEILP2 (n = 187)), as defined in Fig. 1e. Log-transformed average expressions and fold changes are shown. A two-sided Wilcoxon rank-sum test was used to determine significance.
Supplementary Table 2: Genes differentially expressed between Tcf7EGFPnull/− EILPs and wild-type sEILPs in bulk RNA-Seq
Gene expression is shown as the log-transformed average for each sample. Fold changes in expression between TCF-1-deficient EILPs and wild-type sEILPs are indicated.
Supplementary Table 3: Genes differentially expressed between Tcf7EGFPnull/− and wild-type sEILP1s and sEILP2s in scRNA-Seq
The gene expression of TCF-1-deficient and sufficient cells separated by clusters, as shown in Fig. 6c, was compared. Statistics were calculated on n = 270 sEILP1s and n = 276 sEILP2s that were TCF-1 deficient, and n = 615 sEILP1s and n = 187 sEILP2s that were TCF-1 sufficient. Log-transformed average expressions and fold changes are shown. A two-sided Wilcoxon rank-sum test was used to determine significance.
Supplementary Table 4: Genes differentially expressed between Tcf7EGFPnull/− and wild-type sEILP1s separated by pseudotimes in scRNA-Seq
The gene expression of TCF-1-deficient and sufficient sEILP1s separated by pseudotimes, as shown in Supplementary Fig. 7c,d, was compared. Statistics were calculated on n = 224 main sEILP1s and n = 75 alternative sEILP1s that were TCF-1 deficient, and n = 585 main sEILP1s and n = 84 alternative sEILP1s that were TCF-1 sufficient. Log-transformed average expressions and fold changes are shown. A two-sided Wilcoxon rank-sum test was used to determine significance.
Supplementary Table 5: Correlation network
Putative regulatory relationships between controllers and targets are indicated, along with their corresponding maximum absolute correlation coefficient. All cells in the main trajectory of differentiation (n = 2,633) were used to calculate Pearson’s correlations. Only maximum absolute correlations of ≥0.2 were considered, which corresponded to an FDR < 5 × 10–5. The pseudotime lag of expression between a controller and its targets is indicated.
Supplementary Table 6: TCF-1 ChIC-Seq peaks
The coordinates for individual TCF-1 binding peaks, as identified by ChIC-Seq, are indicated and mapped to the nearest gene.
Supplementary Table 7: TCF-1 gene targets
TCF-1 gene targets were identified using the correlation network (Supplementary Table 5), TCF-1 binding (Supplementary Table 6) and Tcf7EGFPnull/− RNA-Seq data (Supplementary Tables 3 and 4).
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Harly, C., Kenney, D., Ren, G. et al. The transcription factor TCF-1 enforces commitment to the innate lymphoid cell lineage. Nat Immunol 20, 1150–1160 (2019). https://doi.org/10.1038/s41590-019-0445-7
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DOI: https://doi.org/10.1038/s41590-019-0445-7
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