Expansion of activated regulatory T cells inversely correlates with clinical severity in septic neonates Eleonora Timperi, PhD, Laura Folgori, MD, Donato.

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Presentation transcript:

Expansion of activated regulatory T cells inversely correlates with clinical severity in septic neonates Eleonora Timperi, PhD, Laura Folgori, MD, Donato Amodio, MD, Maia De Luca, MD, Sara Chiurchiù, MD, Silvia Piconese, PhD, Silvia Di Cesare, MS, Ilenia Pacella, MS, Carmela Martire, MS, Giulia Bonatti, MD, Seila Perrone, MD, Terenzio Boni, MD, Genni Enza Marcovecchio, MS, Antonino Reale, MD, Francesco Parisi, MD, Andrea Dotta, MD, Vincenzo Barnaba, MD, Paolo Rossi, MD, PhD Journal of Allergy and Clinical Immunology Volume 137, Issue 5, Pages 1617-1620.e6 (May 2016) DOI: 10.1016/j.jaci.2015.10.048 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Frequency of activated Treg cells inversely correlates with septic score. A, Activated Treg cell frequency estimated by using flow cytometry as the percentage of CD45RAlowFOXP3high Treg cells among CD4+ T cells (CTRLs = 28, neonates with sepsis = 10, neonates with SIRS = 19, and PEDs = 21). *P < .05 and **P < .01, Mann-Whitney test, 2-tailed. B, Spearman correlation (r) between activated Treg cell/CD4+ T-cell percentage and clinical severity score in septic neonates. *P < .05. C, Left, Representative flow cytometric data (CTRL sample) showing CD45RA versus FOXP3 profile. Right, Overlay of CD39 mean fluorescence intensity of CD45RAlowFOXP3high (activated Treg cell), CD45RAhighFOXP3low (resting Treg cell), and CD45RAlowFOXP3low (nonsuppressive Treg cell) subsets. D, Representative flow cytometric plots of CD39 versus FOXP3 expression in gated Treg cells showing the frequency of CD39+ cells according to AA or AG+GG genotypes in the ENTPD1 gene. E, Frequency of CD39+ cells in gated Treg cells in all cohorts according to AA or AG+GG genotype in the ENTPD1 gene (CTRLs = 23, neonates with sepsis = 10, neonates with SIRS = 15, and PEDs = 21). *P < .05, **P < .01, and ****P < .001, Mann-Whitney test, 2-tailed. F, Frequency of CD39+ cells in gated Tconv cells in all cohorts according to AA or AG+GG genotype in the ENTPD1 gene (CTRL = 23, sepsis = 10, SIRS = 15, and PED = 21). Journal of Allergy and Clinical Immunology 2016 137, 1617-1620.e6DOI: (10.1016/j.jaci.2015.10.048) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Frequency of OX40+ Treg cells is upregulated in septic neonates and neonates with SIRS and inversely correlates with septic score. A, Frequency of OX40+ cells in subdivided CD39+ and CD39− Treg cell subsets in all groups (CTRLs = 32, neonates with sepsis = 11, neonates with SIRS = 20, and PEDs = 21). *P < .05, **P < .01, ***P < .005, and ****P < .0001, Mann-Whitney test, 2-tailed, and Wilcoxon matched pairs test, 2-tailed. B, Spearman correlation (r) between frequency of OX40+ Treg cells and clinical severity score in septic neonates (Table I). *P < .05. C, Frequency of CD120b+ cells in CD39+ and CD39− Treg cells (CTRLs = 5, neonates with sepsis = 6, and neonates with SIRS = 4). *P < .05, Mann-Whitney test, 2-tailed, and Wilcoxon matched pairs test, 2-tailed. D, Pearson correlation (r) between frequency of CD120b+ cells and OX40+ cells within CD39+ Treg cells in all cohorts. **P < .01. E, PBMCs from CTRLs were cultured overnight with or without TNF-α. OX40 mean fluorescence intensity was evaluated in Treg and Tconv cells. *P < .05, paired t test, 2-tailed. F, Spearman correlation (r) between frequency of OX40+ Treg cells and IL-33 plasma concentration in all cohorts. ***P < .005. Journal of Allergy and Clinical Immunology 2016 137, 1617-1620.e6DOI: (10.1016/j.jaci.2015.10.048) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Percentage of Treg and activated Treg cells in neonates with sepsis and those with SIRS. A, Representative flow cytometric data of CTRLs indicating the gating strategy. In CD4+ T cells we evaluated CD127lowFOXP3+ Treg and FOXP3− Tconv cells, and within the Treg cell gate, we evaluated CD45RAlowFOXP3high activated, CD45RAlowFOXP3low nonsuppressive, and CD45RAhighFOXP3low resting Treg cell subpopulations. B, Representative flow cytometric data showing CD127 versus FOXP3 expression (Treg and Tconv cells) in the CTRL, sepsis, SIRS, and PED cohorts. Treg cell frequency (as a percentage) was estimated by means of flow cytometry as the percentage of CD127lowFOXP3+ Treg cells among CD4+ T cells (CTRL = 33, neonates with sepsis = 12, neonates with SIRS = 20, and PEDs = 21). C, Representative flow cytometric data showing CD45RA versus FOXP3 within the Treg cell gate in the CTRL, sepsis, SIRS, and PED cohorts. Journal of Allergy and Clinical Immunology 2016 137, 1617-1620.e6DOI: (10.1016/j.jaci.2015.10.048) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 CD39 expression in CB samples and OX40 expression on Treg and Tconv cells. A, Representative overlay of CD39 mean fluorescence intensity in gated CD4+ cells on Treg and Tconv cells from the CTRL cohort. B, Representative flow cytometric plots of CD127 versus FOXP3 expression in CD4+ T cells from CB samples. C, Overlay of CD39 mean fluorescence intensity in Treg and Tconv cells from CB samples. D, Representative flow cytometric data showing CD45RA versus FOXP3 (upper) and CD39 median fluorescence intensity (lower) in activated, resting, and nonsuppressive Treg cell subsets from CB samples. E, Representative flow cytometric plots of CD39 versus FOXP3 in gated Treg cells, showing the frequency of CD39+ cells according to AA or AG+GG genotype in the ENTPD1 gene in CB samples. F, Frequency of CD39+ cells within the gate of Treg and Tconv cells according to AA or AG+GG genotype in the ENTPD1 gene (CB = 13). **P < .01, Mann-Whitney test, 2-tailed. G, Representative mean fluorescence intensity of OX40 in gated Treg and Tconv cells in CD39+ and CD39− cells from the CTRL cohort. H, Frequency of OX40+ cells in subdivided CD39+ and CD39− Tconv cell subsets (CTRL = 32, neonates with sepsis = 11, neonates with SIRS = 20, and PEDs = 21). **P < .01 and ****P < .0001, Mann-Whitney test, 2-tailed, and Wilcoxon matched pairs test, 2-tailed. Journal of Allergy and Clinical Immunology 2016 137, 1617-1620.e6DOI: (10.1016/j.jaci.2015.10.048) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 IFN-γ and TNF-α production by T cells. A, Representative plots of Helios versus CD39 and versus OX40 in gated Treg cells in the CTRL, sepsis, SIRS, and PED cohorts. B, Representative plots of IFN-γ versus TNF-α in gated CD4+ and CD8+ T cells in the CTRL, sepsis, SIRS, PED, and adult healthy donor (AD) cohorts. C, Representative pie charts (obtained through SPICE analysis) showing proportions of IFN-γ+ or TNF-α+ single- or double-producing cells in gated CD4+ and CD8+ T cells in the CTRL, sepsis, SIRS, PED, and AD cohorts. Legend refers to pie chart arcs. *P < .05, **P < .01, ***P < .005, and ****P < .0001, Student t test referred to IFN-γ+TNF-α+ double-producing cells, calculated for CTRL, sepsis and SIRS compared with PED group and PED group compared with ADs (CTRL = 12, neonates with sepsis = 4, neonates with SIRS = 14, PEDs = 15, and ADs = 6). Journal of Allergy and Clinical Immunology 2016 137, 1617-1620.e6DOI: (10.1016/j.jaci.2015.10.048) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 CD120b expression in Treg cells and IL-33 effects. A, Left, Mean fluorescence intensity of CD120b in Treg and Tconv cells. Middle, Overlay of CD120b mean fluorescence intensity in CD39+ and CD39− Treg cells. Right, Overlay of CD120b mean fluorescence intensity in CD39+OX40+ and CD39+OX40− cells within the Treg cell gate. B, Representative plot of OX40 mean fluorescence intensity in gated Treg and Tconv cells on overnight TNF-α treatment of PBMCs. C, PBMCs from adult healthy donors were cultured overnight with or without IL-33. Mean fluorescence intensity of OX40 was evaluated in CD39+ versus CD39− Treg and Tconv cells. *P < .05 and **P < .01, paired t test, 2-tailed. Journal of Allergy and Clinical Immunology 2016 137, 1617-1620.e6DOI: (10.1016/j.jaci.2015.10.048) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions