Mammalian target of rapamycin inhibition counterbalances the inflammatory status of immune cells in patients with chronic granulomatous disease Aurélie.

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Mammalian target of rapamycin inhibition counterbalances the inflammatory status of immune cells in patients with chronic granulomatous disease Aurélie Gabrion, MSc, Isabelle Hmitou, PhD, Despina Moshous, MD, PhD, Bénédicte Neven, MD, PhD, Alain Lefèvre-Utile, MD, MSc, Jean-Sébastien Diana, MD, MSc, Félipe Suarez, MD, PhD, Capucine Picard, MD, PhD, Stéphane Blanche, MD, Alain Fischer, MD, PhD, Marina Cavazzana, MD, PhD, Fabien Touzot, MD, PhD Journal of Allergy and Clinical Immunology Volume 139, Issue 5, Pages 1641-1649.e6 (May 2017) DOI: 10.1016/j.jaci.2016.08.033 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Analysis of circulating monocyte subsets in patients with CGD. A, Representative dot plot of CD16/CD14 gating on circulating monocytes in patients with CGD versus HCs. B, Absolute numbers of circulating CD16+, intermediate, and CD14+ monocytes in patients with CGD (n = 14) versus HCs (n = 15). C, Representative images of intracytoplasmic staining for IL-1β (upper panel) and TNF-α (lower panel) in patients with CGD versus HCs. D, Geometric mean fluorescence intensity (GMFI) ratio between IL-1β and the isotype control in patients with CGD (n = 14) versus HCs (n = 15). E, GMFI ratio between TNF-α and the isotype control in patients with CGD (n = 14) versus HCs (n = 15). **P < .01 and ***P < .001, Mann-Whitney U test. Extremities of the whiskers boxes represent minimum and maximum values. The bottom and top of the box represent the first and third quartiles, respectively. The horizontal bar in the box represents the median value. Journal of Allergy and Clinical Immunology 2017 139, 1641-1649.e6DOI: (10.1016/j.jaci.2016.08.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Cytokine profile of CD4+ T cells patients with CGD is skewed toward TH17. A, Percentage of IFN-γ–, IL-4–, IL-10–, IL-17A–, and TNF-α–secreting CD4+ T cells evaluated by means of intracellular staining after PMA/ionomycin stimulation in patients with CGD (n = 10) and HCs (n = 8) were stimulated with anti-CD3/CD28 for 48 hours. Supernatants were then collected for cytokine analysis by using a cytometric bead assay (MACSPlex). B, Purified total CD4+ T cells obtained from patients with CGD (n = 10) and HCs (n = 6) were stimulated with anti-CD3/CD28 for 48 hours. Supernatants were then collected for cytokine analysis by using a cytometric bead assay (MACSPlex). *P < .05, **P < .01, and ***P < .001, Mann-Whitney U test. Extremities of the whiskers boxes represent minimum and maximum values. The bottom and top of the box represent the first and third quartiles, respectively. The horizontal bar in the box represents the median value. Journal of Allergy and Clinical Immunology 2017 139, 1641-1649.e6DOI: (10.1016/j.jaci.2016.08.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Expression of IL-17A and RORγt in human peripheral blood neutrophils from patients with CGD or HCs. A, Intracytoplasmic IL-17A staining of total neutrophils in blood of patients with CGD (n = 10) or HCs (n = 8). Representative scatterplot (left panels) and proportion and absolute number of IL-17A–secreting neutrophils in blood (right panels) are shown. B, Intracytoplasmic RORγt staining of total neutrophils in blood of patients with CGD or HCs. Representative scatterplot (left panels) and proportion and absolute number of RORγt-secreting neutrophils (right panels) are shown. **P < .01, Mann-Whitney U test. ns, Not significant. Extremities of the whiskers boxes represent minimum and maximum values. The bottom and top of the box represent the first and third quartiles, respectively. The horizontal bar in the box represents the median value. Journal of Allergy and Clinical Immunology 2017 139, 1641-1649.e6DOI: (10.1016/j.jaci.2016.08.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Reversion of CGD inflammatory status by rapamycin. A, CD14+ monocytes from patients with CGD (n = 15, 18 samples) and HCs (n = 7, 7 samples) were differentiated into macrophages with (gray bars) or without (DMSO, open bars) rapamycin. Supernatant were collected at day +6 after differentiation, and cytokines were analyzed by using a cytometric bead assay (MACSPlex) or ELISA. B, MDMs from patients with CGD (n = 12) and HCs (n = 5) were stimulated for 24 hours with 100 ng/mL LPS in the presence of 10 nmol/L rapamycin (gray bars) or not (DMSO, open bars). Supernatant were collected for cytokines analysis through a cytometric bead assay (MACSPlex) or ELISA. C, MDMs from patients with CGD and HCs were primed with LPS and stimulated for 30 minutes with ATP in the presence or not of 10 mmol/L rapamycin. Caspase-1 activity was determined by using fluorescent inhibitor of active caspase-1 (FLICA). Numbers above bracketed lines indicate percentage of cells with active caspase-1. D, Active caspase-1 in MDMs from 5 patients with CGD treated or not with 10 nmol/L rapamycin quantified by using caspase-1 FLICA. E, Purified total CD4+ T cells obtained from patients with CGD (n = 6) and HCs (n = 5) were stimulated with anti-CD3/CD28 for 48 hours in the presence of 10 nmol/L rapamycin (gray bars) or not (DMSO, open bars). Supernatants were then collected for cytokine analysis by using a cytometric bead assay (MACSPlex). F and G, CD14+ monocytes from patients with CGD (n = 8) were treated for 24 hours with 10 nmol/L rapamycin and increasing dose of anakinra (ie, 0, 40, and 400 ng/mL) before 4 hours of stimulation with LPS. Monocytes were then analyzed for IL-1β (Fig 4, F) and TNF-α secretion (Fig 4, G). *P < .05, **P < .01, and ***P < .001, Mann-Whitney U test or Wilcoxon paired t test. Journal of Allergy and Clinical Immunology 2017 139, 1641-1649.e6DOI: (10.1016/j.jaci.2016.08.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 TH17 cytokine profile of CD4+ T cells from patients with CGD. A and C, Representative intracellular staining of IL-17A (Fig E1, A) and TNF-α (Fig E1, C) in unstimulated CD4+ T cells of patients with CGD and HCs. B and D, Intracellular content of IL-17A (Fig E1, B) and TNF-α (Fig E1, D) in unstimulated CD4+ T cells of patients with CGD (n = 14) and HCs (n = 10) evaluated based on the ratio between the geometric mean fluorescence intensity (GMFI) of the specific staining versus isotype control. *P < .05 and **P < .01, Mann-Whitney U test). Extremities of the whiskers boxes represent minimum and maximum values. The bottom and top of the box represent the first and third quartiles, respectively. The horizontal bar in the box represents the median value. Journal of Allergy and Clinical Immunology 2017 139, 1641-1649.e6DOI: (10.1016/j.jaci.2016.08.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Effect of rapamycin on MDMs from patients with CGD. A, CD14+ monocytes from patients with CGD (n = 15, 18 samples) and HCs (n = 7, 7 samples) were differentiated into macrophages with or without (DMSO) rapamycin. Supernatants were collected at day +6 after differentiation, and cytokines were analyzed by using a cytometric bead assay (MACSPlex) or ELISA. B, MDMs from patients with CGD (n = 12) and HCs (n = 5) were stimulated for 24 hours with 100 ng/mL LPS in the presence or not (DMSO) of 10 nmol/L rapamycin. Supernatants were collected for cytokine analysis by using a cytometric bead assay (MACSPlex) or ELISA. C, MDMs from patients with CGD treated or not with 10 nmol/L rapamycin were analyzed for S235-236 phospho-S6 ribosomal protein IL-1β, IL-6, and TNF-α expression by means of intracytoplasmic staining. D, Geometric mean fluorescence intensity (GMFI) ratio between IL-1β or TNF-α and the isotype control in MDMs from patients with CGD (n = 5) versus HCs (n = 4) at day +6 after differentiation. E, Expression of CD11b, CD68, HLA-DR, and CD86 by MDMs from patients with CGD after differentiation in the presence or absence (DMSO) of 10 nmol/L rapamycin. **P < .01, Mann-Whitney U test or Wilcoxon paired t test. Extremities of the whiskers boxes represent minimum and maximum values. The bottom and top of the box represent the first and third quartiles, respectively. The horizontal bar in the box represents the median value. Journal of Allergy and Clinical Immunology 2017 139, 1641-1649.e6DOI: (10.1016/j.jaci.2016.08.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 LC3 staining in MDMs from patients with CGD as a surrogate marker of autophagy induction. A, Representative LC3 staining in MDMs from patients with CGD after rapamycin. B, Percentage of cells with positive staining for LC3 with or without (DMSO) treatment with 10 nmol/L rapamycin (data are representative of 3 experiments). Journal of Allergy and Clinical Immunology 2017 139, 1641-1649.e6DOI: (10.1016/j.jaci.2016.08.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions