Tolerogenic signaling by pulmonary CD1c+ dendritic cells induces regulatory T cells in patients with chronic obstructive pulmonary disease by IL-27/IL-10/inducible.

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Tolerogenic signaling by pulmonary CD1c+ dendritic cells induces regulatory T cells in patients with chronic obstructive pulmonary disease by IL-27/IL-10/inducible costimulator ligand Maria Tsoumakidou, MD, PhD, Sofia Tousa, MD, Maria Semitekolou, PhD, Panagiota Panagiotou, MD, Anna Panagiotou, MD, Ioannis Morianos, PhD, Eleni Litsiou, PhD, Aikaterini I. Trochoutsou, MSc, Maria Konstantinou, MSc, Konstantinos Potaris, MD, PhD, Joseph Footitt, MD, PhD, Patrick Mallia, MD, PhD, Spyros Zakynthinos, MD, PhD, Sebastian L. Johnston, MD, PhD, Georgina Xanthou, PhD Journal of Allergy and Clinical Immunology Volume 134, Issue 4, Pages 944-954.e8 (October 2014) DOI: 10.1016/j.jaci.2014.05.045 Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Characterization of CD1c+DCCOPD. A and B, Surface markers. Fig 1, A, Representative histogram plots relative to fluorescence-minus-one (FMO) control (percentages shown). Fig 1, B, Cumulative mean fluorescence intensities (MFIs; DCN-Sm, n = 5-7; DCSM, n = 7-13; DCCOPD, n = 7-14). Lines are at medians. C, Alexa Fluor–ovalbumin endocytosis. Relative MFI (rMFI) = (MFI37°C − MFI4°C)/MFI4°C (DCN-Sm, n = 3; DCSM, n = 4; DCCOPD, n = 4). Values are presented as means ± SEMs. D and E, Surface markers before/after LPS stimulation (DCN-Sm, n = 4; DCSM, n = 7; DCCOPD, n = 7; Fig 1, D) and cytokines in culture supernatants (DCN-Sm, n = 3; LPS-DCSM, n = 10-12; LPS-DCCOPD, n = 6-8; Fig 1, E). Values are presented as means ± SEMs. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2014 134, 944-954.e8DOI: (10.1016/j.jaci.2014.05.045) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Lung CD1c+DCCOPD are immunosuppressive. A and B, Tolerogenic surface molecules. Representative histogram plots relative to fluorescence-minus-one (FMO) control (percentages shown; Fig 2, A) and cumulative data of DCN-Sm (n = 5), DCSM (n = 5), and DCCOPD (n = 6; Fig 2, B). C, Tritiated thymidine incorporation/IFN-γ by allogeneic CD4+ T cells stimulated by CD1c+ DCs (DCN-Sm, n = 5; DCSM, n = 10; DCCOPD, n = 10). D and E, Tritiated thymidine incorporation/IFN-γ by allogeneic CD4+ T cells stimulated by APCs (MLRs) and CD1c+ DCs. Fig 2, D, Representative (DCN-Sm, n = 2; DCSM, n = 2; DCCOPD, n = 2). Values are presented as means ± SEMs. Fig 2, E, Cumulative (2 × 103 CD1c+ DCs; DCN-Sm, n = 5; DCSM, n = 6; DCCOPD, n = 6). Lines are at medians. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2014 134, 944-954.e8DOI: (10.1016/j.jaci.2014.05.045) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 CD1c+DCCOPD induce IL-10–secreting T cells. A, Surface markers on CD1c+ DC–primed allogeneic CD4+ T cells. Representative histogram plots are shown (T[DCSM], n = 3; T[DCCOPD], n = 3). FMO, Fluorescence-minus-one. B, Representative contour plots of IL-10 and summary data (right; T[DCSM], n = 5; T[DCCOPD], n = 6). C, TH cell transcriptional profile analyzed by using quantitative real-time RT-PCR. Results are presented relative to GAPDH. Data are representative of T(DCSM) (n = 3) and T(DCCOPD) (n = 4). D, Representative CFSE plots of CD1c+ DC–primed autologous lung CD3+CD4+ T cells and summary data (right; T[DCSM], n = 5; T[DCCOPD], n = 6). White-filled histograms indicate T cells alone. E, Representative contour plots of IL-10 by CD1c+ DC–primed autologous lung CD3+CD4+ T cells and summary data (right; T[DCSM], n = 6; T[DCCOPD], n = 5). Percentages are shown on all plots. **P < .01. Journal of Allergy and Clinical Immunology 2014 134, 944-954.e8DOI: (10.1016/j.jaci.2014.05.045) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 CD1c+DCCOPD-primed T cells suppress T-cell responses. A, Tritiated thymidine incorporation/IFN-γ by allogeneic CD4+ T cells stimulated with APCs (1°MLR) in the presence of T(DCs) (T[DCSM], n = 8; T[DCCOPD], n = 8). Lines are at medians. B, Allogeneic CD4+ T cells were stimulated by APCs (1°MLR) and then purified and restimulated by allogeneic APCs (2°MLR) in the presence of T(DCs). C, T(DCs) were restimulated with anti-CD3/CD28 mAbs. B-D, Tritiated thymidine incorporation/IFN-γ, as in Fig 4, A. Representative (T[DCSM], n = 2; T[DCCOPD], n = 2). Values are presented as means ± SEMs. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2014 134, 944-954.e8DOI: (10.1016/j.jaci.2014.05.045) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 CD1c+DCCOPD induce Treg cells through IL-27, IL-10, and ICOS-L. A, CM from allogeneic CD4+ T cells cultured with CD1c+ DCs was added to fresh MLRs (CM-DCSM, n = 6; CM-DCCOPD, n = 8). Lines are at medians. B, Tritiated thymidine incorporation by T cells is shown (representative: CM-DCSM, n = 3; CM-DCCOPD, n = 3). Values are presented as means ± SEMs. C, CD1c+ DC–primed T cells generated in the presence of blocking antibodies were isolated and added to fresh MLRs, as in Fig 4, A. Tritiated thymidine incorporation/IFN-γ is shown (representative: T[DCSM], n = 2; T[DCCOPD], n = 2). Values are presented as means ± SEMs. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2014 134, 944-954.e8DOI: (10.1016/j.jaci.2014.05.045) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Exposure to a COPD lung micromilieu endows CD1c+DCSM with tolerogenic properties. A, Histogram plots of tolerogenic surface markers on CD1c+DCSM (percentages shown). B, Quantitative real-time PCR analysis of IL-27p28 expression relative to GAPDH. C, Allogeneic CD4+ T cells were stimulated with LH-treated CD1c+DCSM, as indicated. Values are presented as means ± SEMs. Fig 6, A-C, Representative (LHSM, n = 3; LHCOPD, n = 3). *P < .05. Journal of Allergy and Clinical Immunology 2014 134, 944-954.e8DOI: (10.1016/j.jaci.2014.05.045) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 COPD lung IL-27 and IL-10 levels are increased at baseline and upregulated on experimentally induced viral exacerbations. A, IL-10 and IL-27 levels in BAL fluid of never smokers (n = 13; N-Sm), smokers without COPD (n = 12; SM), and patients with COPD (n = 16-19) at baseline. B, BAL IL-27 and IL-10 levels at days 0 and 7 after infection (N-Sm, n = 5-6; SM, n = 7; COPD, n = 7-8). Lines are at medians. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2014 134, 944-954.e8DOI: (10.1016/j.jaci.2014.05.045) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Numbers of CD1c+ DCs among 106 total lung cells in never smokers (N-SM; n = 7), former smokers without COPD (SM; n = 15), and patients with COPD (n = 16) are shown. Each dot represents a single donor. Lines are at medians. Journal of Allergy and Clinical Immunology 2014 134, 944-954.e8DOI: (10.1016/j.jaci.2014.05.045) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Fluorescence-activated cell sorting analysis of CD1c+ DC–primed T cells. A-C, Representative density plots showing transcription factor expression gated on CD3+CD4+ T cells are shown, as indicated (T[DCSM], n = 4; T[DCCOPD], n = 4). D, The percentages of TBX21+, GATA-3+, and RORC+ cells on gated CD4+ T cells are shown as well (right). Journal of Allergy and Clinical Immunology 2014 134, 944-954.e8DOI: (10.1016/j.jaci.2014.05.045) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 CD1c+DCCOPD-exposed lung T cells respond poorly to secondary polyclonal stimulation in vitro. Lung CD1c+DCCOPD were cocultured with CFSE-labeled CD3+ T cells isolated from the same lung tissue explants. CD3+ T cells were isolated, washed, and restimulated with anti-CD3 and anti-CD28. T-cell proliferation was assessed by measuring CFSE dilution. Gray-filled histograms represent lung T cells cultured with autologous CD1c+DCCOPD. White-filled histograms represent CD1c+DCCOPD-primed lung T cells restimulated with anti-CD3 and anti-CD28. Data are representative of 3 independent experiments. Journal of Allergy and Clinical Immunology 2014 134, 944-954.e8DOI: (10.1016/j.jaci.2014.05.045) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Lung CD1c+DCCOPD do not stimulate autologous lung-resident CD8+ T-cell responses. A, Lung CD1c+DCSM or CD1c+DCCOPD were cocultured with CFSE-labeled CD3+ T cells isolated from the same lung tissue explants. CD3+CD8+ T-cell proliferation was assessed by measuring CFSE dilution. Representative CFSE plots are shown (left), and numbers in plots indicate percentages of CFSE−/low cells. White-filled histograms represent T cells cultured in the absence of DCs. Summary data (right) show percentages of proliferating T cells from 11 independent experiments (T [DCSM], n = 5; T[DCCOPD], n = 6). B, Intracellular IL-10 expression on gated lung CD3+CD8+ T cells stimulated as above is shown. Representative contour plots are shown (left), and numbers in plots indicate percentage of positive cells. Summary data (right) show percentages of CD8+IL-10+ T cells from 11 independent experiments (T[DCSM], n = 6; T [DCCOPD], n = 5). Lines are at medians. Statistical significance was obtained by using the Mann-Whitney U test: **P < .01. Journal of Allergy and Clinical Immunology 2014 134, 944-954.e8DOI: (10.1016/j.jaci.2014.05.045) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 IL-10, ICOS, and PD-1 expression on CD4+ T cells primed by lung CD1c+DCCOPD depends on IL-27, IL-10, and ICOS-L signaling. Purified lung CD1c+ DCs of patients with COPD were cocultured with allogeneic naive CD4+ T cells, as indicated. T(DCCOPD) were isolated and analyzed by using flow cytometry. Percentages of IL-10+, ICOS+, PD-1+, and PD-L1+ cells on gated CD4+ T cells are shown. Data are representative of 2 independent experiments. Journal of Allergy and Clinical Immunology 2014 134, 944-954.e8DOI: (10.1016/j.jaci.2014.05.045) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions