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Volume 22, Issue 7, Pages 1388-1395 (July 2014) Ultra-low Dose Interleukin-2 Promotes Immune-modulating Function of Regulatory T Cells and Natural Killer Cells in Healthy Volunteers Sawa Ito, Catherine M Bollard, Mattias Carlsten, Jan Joseph Melenhorst, Angélique Biancotto, Ena Wang, Jinguo Chen, Yuri Kotliarov, Foo Cheung, Zhi Xie, Francesco Marincola, Kazushi Tanimoto, Minoo Battiwalla, Matthew J Olnes, Shira Perl, Paula Schum, Thomas E Hughes, Keyvan Keyvanfar, Nancy Hensel, Pawel Muranski, Neal S Young, A John Barrett Molecular Therapy Volume 22, Issue 7, Pages 1388-1395 (July 2014) DOI: 10.1038/mt.2014.50 Copyright © 2014 The American Society of Gene & Cell Therapy Terms and Conditions

Figure 1 Chronological changes in Tregs subsets after ultra-low dose (ULD) IL-2. (a) %FoxP3+CD4 Tregs were significantly increased and peaked at day 4 (mean 3.53 ± 1.17% at day 0 versus 5.68 ± 1.56% at day 4; P < 0.0001). (b,c) Helios+FoxP3+Tregs were significantly increased by day 2 (mean 2.19 ± 1.17% at day 0 versus 3.51 ± 1.03% at day 2; P = 0.004) followed by Helios−FoxP3+Tregs (mean 1.36 ± 0.71% at day 0 versus 1.86 ± 1.16% at day 3; P = 0.01). Both subsets of Tregs significantly expanded, peaking at day 4 and remaining significantly higher than baseline until day 7. (d) Expansion of Helios+FoxP3+Tregs was significantly higher when donors received 100,000 and 200,000 IU/m2 IL-2 compared to 50,000 IU/m2 (P < 0.001 and P = 0.01 at day 4 respectively). (e) Ki67 was significantly induced in Helios+FoxP3+Tregs specifically in 100,000 and 200,000 IU/m2 IL-2 compared to 50,000 IU/m2 (P = 0.03 and P = 0.01 at day 4 respectively). (f) HLA-DR was significantly induced in Helios+FoxP3+Tregs specifically in 100,000 and 200,000 IU/m2 IL-2 compared to 50,000 IU/m2 (P = 0.008 and P = 0.04 at day 4 respectively). (g) The representative flow cytometry data showed expansions of FoxP3+CD4 Tregs in both Helios fractions in healthy volunteer receiving ULD IL-2 (200,000 IU/m2). Molecular Therapy 2014 22, 1388-1395DOI: (10.1038/mt.2014.50) Copyright © 2014 The American Society of Gene & Cell Therapy Terms and Conditions

Figure 2 Chronological changes in natural killer (NK) cell subsets after ultra-low dose (ULD) IL-2. (a) CD56bright NK cells were significantly increased at day 7 (9.0 ± 4.7% at day 0 versus 12.7 ± 5.8% at day 7; P = 0.001). (b) %Ki67 in NK cell was markedly increased at day 4 (P < 0.0001). (c,d) %Ki67 was significantly induced in CD56bright NK cells compared to CD56dimNKG2A+KIR−, and CD56dimKIR+CD57+ NK populations (26.4 ± 11.4% Ki67+ in CD56bright NK, versus 10.1 ± 7.3% in CD56dimNKG2A+ KIR−NK, 6.1 ± 2.9% CD56dimKIR+CD57+ NK at day 4; P < 0.0001) especially in the cohort of 200,000 IU/m2. Molecular Therapy 2014 22, 1388-1395DOI: (10.1038/mt.2014.50) Copyright © 2014 The American Society of Gene & Cell Therapy Terms and Conditions

Figure 3 In vitro functions of Tregs and natural killer (NK) cells after ultra-low dose (ULD) IL-2. (a) Tcons (CD3+CD4+CD25lowCD127high) equally expressed CD154 through anti-CD3/CD28-coated bead stimulation in pre- and post-IL-2 samples (CD154 expression 52.3 ± 17.5% pre-IL-2 Tcons versus 52.8 ± 17.9% post-IL-2 Tcon; P = 0.86). (b) The suppressive capacity of Tregs on CD154 activation of autologous Tcons was significantly increased in post-IL-2 samples (% suppression 14.0 ± 6.9% pre-IL-2 versus 19.9 ± 8.8% post-IL-2 at Tregs:Tcons ratio 1:1; P = 0.02). (c) Significantly increased interferon (IFN)-γ productions in post-IL-2 NK cells was observed compared to pre-IL-2 NK cells especially in the CD56brightNK cell subset (mean %IFN-γ production 12.0 ± 2.1% pre-IL-2 versus 21.0 ± 4.2% post-IL-2 with IL-12+IL15 and K562 stimulation; P = 0.009). (d) CD107a expression was not significantly different pre- versus post-IL-2 injections (mean %CD107a expression in CD56dimNK cells, 9.6 ± 3.6% pre-IL-2 versus 9.3 ± 3.7% post-IL-2 with IL-12+IL15 and K562 stimulation; P = 0.75). Molecular Therapy 2014 22, 1388-1395DOI: (10.1038/mt.2014.50) Copyright © 2014 The American Society of Gene & Cell Therapy Terms and Conditions

Figure 4 Genes differentially expressed by ultra-low dose (ULD) IL-2 in healthy volunteers. (a) Functional annotation of ULD IL-2 related genes: functional relationships are annotated to the genes differentially expressed on day 4 after ULD IL-2 using IPA Ingenuity Path Designer. (b) Time-course analysis of differentially expressed genes after ULD IL-2: hierarchical clustering of genes differentially expressed after ULD IL-2 is shown in a heatmap. Days are represented in the columns and probe sets in the rows. Molecular Therapy 2014 22, 1388-1395DOI: (10.1038/mt.2014.50) Copyright © 2014 The American Society of Gene & Cell Therapy Terms and Conditions