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ACB Figure S1. Analysis of Lineage Negative Pbmcs. (A A C Lin CD16 Before sort A - Before sort Lin FSC Sorted CD56hiNK cells Sorted Lin-CD45+CD56-CD127- cells Sorted Sorted CD56dimNK cells Lin-CD45+CD56-CD127+ Cells (ILCs) CD56 CD127 Sorted CD56-NK cells B A - Lin Sorted ILCs FSC CD117 CD56 CD127 CRTH2 CD56 CD127 Figure S1. Analysis of lineage negative PBMCs. (A) Sorting strategy for Lin–CD45+CD56–CD127– and Lin–CD45+CD56–CD127+cells. (B) Lin–CD45+CD56–PBMCs were detected with CD127, CD117 and CRTH2. (C) Sorting strategy for CD56–, CD56dim and CD56hiNK cells and ILCs. All data were generated using blood from healthy donors. Related to Figure 1. 3000 250 600 A 20000 IL7R KIT 800 IL4R IL1RL1 CCR7 200 600 15000 2000 400 150 10000 400 100 1000 200 5000 200 50 0 0 0 0 0 800 8000 150 GPR183 TCF7 MYC 600 6000 100 - Normalized counts Normalized CD56 NK 400 4000 CD56dimNK hi 50 CD56 NK 200 2000 ILC 0 0 0 B Areg C Gata3 D Rorc E Tbx21 *** ** 10000 *** 40000 20000 *** 8000 *** *** *** * * *** ** 8000 ** ns*** *** 30000 *** 15000 6000 6000 20000 10000 4000 4000 10000 5000 2000 2000 Normalized counts Normalized 0 0 0 0 1 2 p 3 s 1 2 p 3 s 1 2 p 3 s 1 2 p 3 s C C 2 C ll C C 2 C ll C C 2 C ll C C 2 C ll L L C L e L L C L e L L C L e L L C L e I I L I c I I L I c I I L I c I I L I c I K I K I K I K N N N N 800 F 15000 JAK1 400 IRF8 6000 DAP12 SYK 2000 LYN 300 600 1500 10000 4000 200 400 1000 5000 2000 100 200 500 - 0 0 0 0 CD56 NK 0 CD56dimNK hi 2500 FYN 8000 KLRD1 8000 KLRK1 1000 KLRC2 FCER1G CD56 NK 4000 ILC 2000 800 6000 6000 3000 Normalized counts Normalized 1500 600 4000 4000 2000 1000 400 2000 2000 1000 500 200 0 0 0 0 0 5000 50000 8000 1000 G RPS9 RPL9 RPL32 EIF3D 15000 EEF2 4000 40000 800 6000 - 600 10000 CD56 NK 3000 30000 CD56dimNK 4000 hi 2000 20000 400 CD56 NK 5000 ILC 2000 1000 10000 200 0 0 0 0 Normalized counts Normalized 0 600 H 3000 KIT 1000 STAT5B 10000 GATA3 2000 BCL2 500 IL1R1 IL2RA 8000 400 800 1500 400 2000 600 6000 300 1000 200 400 4000 200 1000 500 200 2000 100 0 0 0 0 0 0 400 5000 800 IL6R 300 IL17RB IL23A 3000 IL32 RORA 4000 300 600 200 2000 3000 Normalized counts Normalized hi 200 CD56 NK 400 2000 ILC 100 1000 100 200 1000 0 0 0 0 0 Figure S2. Representative transcripts of NK cells and ILCs. (A) Representative genes shared between CD56hiNK cells and ILCs. (B-E) DESeq2 normalized counts of Areg (B), Gata3 (C), Rorc (E), and Tbx21 (E), in mouse ILC1s (n=7), ILC2s (n=12), ILC2ps (n=2), ILC3s (n=19) and NK cells (n=19). Data are mean ± s.e.m., two-tailed unpaired t-test. *p<0.05, **p<0.01, ***p<0.001. (F-H) Enriched genes in all human NK cell subsets compared with ILCs (F), enriched genes in ILCs and CD56hiNK cells compared with CD56– and CD56dimNK cells (G), enriched genes in ILCs compared with CD56hiNK cells (H). For (A, F-H), Data were generated using blood from healthy donors. For (B-E), Mouse data was derived from GSE77695, GSE109125, and GSE116092. Related to Figure 2. A ILC specific NK specific 0-1.5 0-9 0-10 0-6 0-1.5 0-9 0-10 0-6 0-1.5 0-9 0-10 0-6 0-1.5 0-9 0-10 0-6 PTGDR2 TNFRSF25 EOMES NKG7 0-15 0-8 0-6 0-10 0-15 0-8 0-6 0-10 0-15 0-8 0-6 0-10 0-15 0-8 0-6 0-10 IL2RB SOCS3 IL23A CST7 0-2 0-3 0-8 CD56- NK 0-2 0-8 0-3 CD56dimNK 0-8 0-2 0-3 CD56hiNK ILC 0-2 0-3 0-8 TBX21 IL32 RORC B GEO accession number: GSE77695, GSE109125, and GSE116092 10) - mouse ILC1 mouse ILC2/ILC2p mouse ILC3 mouse NK ata range (each row ata height range row 1 is(each d Areg Figure S3. Chromatin accessibility in NK cells and ILCs. (A) ATAC-Seq signal of gene loci associated with human NK cells and ILCs. (B) ATAC- Seq signal from the Areg promoter region in mouse ILC1s, ILC2s, ILC2ps, ILC3s and NK cells, data was derived from GSE77695, GSE109125, and GSE116092. Related to Figure 2. RUNX3 KO1, Editing rate=91% A Lin-TBX21+ Control KO RUNX3 KO1 RUNX3 KO2 RUNX3 KO2, Editing rate=91% Normalized to mode Normalized RUNX3 B No electro Control KO RUNX3 KO1 RUNX3 KO2 A - FSC AREG C HIV-1+ HIV-1 negative Viremic ART Controller E * CD127 * 15000 *** MFI 10000 CD16 Gated on Lin-CD56- CD56 5000 HIV-1+ D HIV-1 negative Viremic ART Controller 0 dim 56 CD56 NK CD HIV-1- HIV-1+ (viremic) HIV-1+ (ART) HIV-1+ (controller) CD16 Gated on Lin- Figure S4. CD56–NK cells are expanded in HIV-1 infection. (A) Detection of RUNX3 editing rate by ICE analysis (https://ice.synthego.com/) (left panel), and protein in NK cells by flow cytometry after control (AAVS1) or RUNX3 knockout (right panel). (B) Detection of NK cells produced AREG after IL-12+IL-15+IL-18 stimulation for 16 hrs from control or RUNX3 knockout groups. (C) Detection of ILCs and CD56–NK cells from indicated groups. (D) Detection of CD56dim and CD56– NK cells in indicated groups. (E) Detection of CD56 MFI in CD56dimNK cells in indicated groups (n=20 for each group). Data are mean ± s.e.m., *p<0.05, ***p<0.001. For (A-C), data were derived from healthy donors. For (C-E), cohort was described in Supplementary Table 5. Related to Figure 4 and 5. A PBMC -CD3 -CD4 -CD8 -CD19 -CD20 CD127 -CD14 -CD34 -CD33 -DC-SIGN -BDCA3 -CD11b CD16 Gated on Lin-CD56- B Data 1 C *** D ns *** 20000 *** *** NK NK NK *** 10000 dim 15000 dim 15000 No IL-2 dim IL-2 No treatment 7500 Isotype 10000 10000 IL-2 + isotype control Anti-IL-2 5000 IL-2 + anti-IL-2 5000 5000 2500 CD56 of CD56 CD56 MFI 0 CD56 of CD56 CD56 MFI CD56 MFI of of CD56 MFI CD56 PBMC CD4-PBMC PBS IL-2 E F G 10000 + 100 NK CD16 dim 80 Blood TBX21 - ** ** 60 5000 40 20 % Live Lin Live in %cell Spleen MFI of CD56 of CD56 in CD56 MFI 0 0 2 9 6 b 0 2 9 6 0 O 9 9 0 i 5 O 9 9 0 ib 5 S - 4 2 n 5 S - 4 2 n 5 M 8 7 2 rl 0 M 8 7 2 rl 0 8 1 - e 9 8 1 - e 9 D 1 5 K x 6 D 1 5 K x 6 C 1 o P C 1 M o P S M v S v C a C A a A R R H Liver A - FSC PBS CD56 I ** NK 15000 dim IL-2 10000 MFI of of CD56 MFI 5000 CD56 IFNg Control Rapa Figure S5. CD4+T cells and IL-2 signaling are required for NK cell stability. (A) Specific cell types were depleted from PBMCs by magnetic beads based on surface markers as indicated, cultured for 5 days, then Lin–CD56–PBMCs were detected with CD127 and CD16 by flow cytometry. (B) PBMC or CD4–PBMCs were cultured for 5 days, CD56 MFI in CD56dimNK cells were detected (n=7). (C) CD56 MFI in CD56dimNK cells was detected from CD4–PBMCs in the presence or absence of IL-2 (10ng/ml) combined with or without IL-2 neutralizing antibody (4ug/ml) (n=7). (D) CD56 MFI in CD56dimNK cells was detected from PBMCs after treatment with isotype or IL-2 neutralizing antibody (4ug/ml) for 5 days (n=10). (E, F) CD56 MFI in CD56dimNK cells (E) and live cell percentage in Lin–TBX21+ cells (F) were detected from PBMCs after treatment with c188-9 (STAT3i), AS-1517499 (STAT6i), MK-2206 (AKTi), Ravoxertinib (ERK1/2i) and CP690550 (JAK3i) for 5 days (n=4). (G, H) CD56 (G) or IFN-γ production (H) from human NK cells in humanized NSG mice were detected as Figure 5K and 5L. (I) PBMCs were treated with or without rapamycin (10nM), the MFI of CD56 in CD56dimNK cells was detected (n=7). Data are mean ± s.e.m., two-tailed paired t-test. ns, not significant, **p<0.01, ***p<0.001. All data were generated using blood from healthy donors. Related to Figure 5 and 7. Table S1 | DEgenes of CD127-vs CD127+ and reactome analysis DEgenes of CD127-vs CD127+ ID padj log2FC pvalue NCR1 2.39E-07 -5.71272 4.18E-09 PDGFRB 9.76E-09 -5.35432 1.31E-10 KRT86 0.00144 -5.28195 8.93E-05 CCNJL 2.45E-09 -5.2332 2.94E-11 SLC1A7 4.32E-07 -5.15736 8.09E-09 IDO1 0.00767 -5.144 0.00067867 RBPMS2 0.00078 -5.00679 4.35E-05 CMKLR1 7.31E-11 -4.93801 6.81E-13 BAALC 0.00017 -4.92973 7.28E-06 LILRA4 3.62E-05 -4.82507 1.27E-06 B3GNT7 1.31E-18 -4.66502 3.98E-21 JCHAIN 0.0002 -4.64785 8.82E-06 PRSS23 6.58E-22 -4.60712 1.31E-24 PODN 0.00096 -4.49081 5.55E-05 LAIR2 9.37E-15 -4.42081 5.52E-17 ADGRG1 5.45E-32 -4.41104 1.56E-35 PALLD 1.62E-07 -4.41056 2.72E-09 SLCO4C1 5.24E-17 -4.40509 2.29E-19 KIFC3 3.39E-13 -4.38642 2.39E-15 GNAL 3.38E-08 -4.38244 5.04E-10 KLRF1 5.02E-11 -4.34724 4.53E-13 CX3CR1 6.50E-09 -4.32492 8.53E-11 RAMP1 1.05E-05 -4.32201 3.04E-07 GUCY1B3 6.91E-06 -4.31063 1.86E-07 CD38 5.01E-19 -4.25548 1.48E-21 SH2D1B 1.34E-31 -4.23675 6.38E-35 NME8 2.83E-12 -4.19778 2.26E-14 CD160 3.39E-38 -4.16578 3.22E-42 GZMH 5.96E-20 -4.13445 1.59E-22 CXCR2 5.01E-16 -4.11615 2.43E-18 MEIS1 0.00063 -4.11336 3.39E-05 SPON2 1.20E-30 -4.08081 1.14E-33 AKR1C3 3.70E-31 -4.04435 2.11E-34 BNC2 5.79E-10 -4.04304 6.27E-12 LOC100129083 4.50E-05 -4.0214 1.63E-06 PROS1 0.00033 -3.98934 1.61E-05 CNTLN 1.39E-05 -3.95794 4.18E-07 FGFBP2 1.18E-23 -3.93227 2.02E-26 ALOX12 0.00514 -3.92196 0.00042286 FCRL2 2.20E-06 -3.90133 4.95E-08 FAT4 2.31E-05 -3.88324 7.47E-07 MLC1 0.00073 -3.88047 3.97E-05 GFOD1 7.27E-18 -3.85316 2.63E-20 LGALS9B 6.23E-05 -3.84744 2.35E-06 KIR3DL3 0.00273 -3.81906 0.00019282 S1PR5 1.77E-33 -3.81311 3.37E-37 NMUR1 3.33E-18 -3.80279 1.14E-20 ATP9A 3.07E-05 -3.79097 1.06E-06 HAVCR2 6.48E-16 -3.78213 3.33E-18 SETBP1 1.71E-07 -3.78152 2.90E-09 TTC38 2.47E-19 -3.76069 6.80E-22 ADGRA2 2.89E-05 -3.75428 9.81E-07 MKI67 2.87E-13 -3.74924 1.99E-15 CCL3 0.00178 -3.73336 0.00011532 GZMB 0.00039 -3.73228 1.94E-05 AKAP5 3.87E-10 -3.73051 4.09E-12 ENC1 1.33E-13 -3.72183 8.71E-16 SYNGR1 2.35E-13 -3.69786 1.58E-15 RHOBTB3 2.84E-19 -3.61923 8.10E-22 GPR153 5.32E-06 -3.6068 1.37E-07 LGR6 2.13E-05 -3.58387 6.74E-07 FCGR3A 1.94E-18 -3.58006 6.27E-21 ERBB2 0.00018 -3.56817 7.99E-06 IGLL5 0.00678 -3.56325 0.00058773 KIR2DS4 0.00015 -3.53063 6.36E-06 PRF1 8.09E-29 -3.52556 9.23E-32 CCL4 1.20E-30 -3.49276 1.03E-33 IGFBP7 6.15E-13 -3.47647 4.45E-15 ASPM 0.00097 -3.45713 5.65E-05 KIR3DL1 0.00073 -3.4558 4.01E-05 PPP1R14A 0.00093 -3.45206 5.36E-05 DAB2 5.45E-14 -3.4465 3.37E-16 CHST2 2.79E-05 -3.43097 9.40E-07
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