Staphylococcal enterotoxin A–activated regulatory T cells promote allergen-specific TH2 response to intratracheal allergen inoculation Wei-ping Zeng,

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Presentation transcript:

Staphylococcal enterotoxin A–activated regulatory T cells promote allergen-specific TH2 response to intratracheal allergen inoculation Wei-ping Zeng, PhD, Margaret M. McFarland, MS, Baohua Zhou, PhD, Silva Holtfreter, Dr rer nat, Susan Flesher, MD, Ambrose Cheung, MD, Avishek Mallick, PhD Journal of Allergy and Clinical Immunology Volume 139, Issue 2, Pages 508-518.e4 (February 2017) DOI: 10.1016/j.jaci.2016.04.033 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Regulation of TH differentiation of OVA-specific CD4 T cells by SEA. A, OVA-specific naive CD4 Tcon cells (CD4+CD62LhighKJ126+GFP−) from DO11.10.Foxp3.GFP mice were stimulated with APCs plus OVA323-339 peptide, IL-12, and SEA in the presence or absence of naive Treg cells (CD4+CD62LhighKJ126−GFP+) from BALB/c.Thy1.1.Foxp3.GFP mice. Cells were analyzed for cytokine expression on day 6 of culture. B, Experiments were set up as in Fig 1, A, except that naive antigen-nonspecific CD4 Tcon cells of BALB/c.Thy1.1.Foxp.GFP mice were used in the cocultures. After the differentiation culture, cells were stimulated with phorbol 12-myristate 13-acetate and ionomycin and analyzed for intracellular cytokine expression by using flow cytometry. Dot plots of IL-13 and IFN-γ expression in CD4+KJ126+GFP− cells of representatives of 3 experiments are shown. Numbers in dot plots are percentages of cells. Journal of Allergy and Clinical Immunology 2017 139, 508-518.e4DOI: (10.1016/j.jaci.2016.04.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 IL-4 expression by SEA-activated Treg cells. A, Naive Treg cells from BALB/c.Foxp3.GFP mice mixed with APCs or APCs alone were stimulated SEA in the presence of IL-12. On day 4, IL-4 in culture supernatants was measured by using ELISA. B, Ex vivo splenic cells of BALB/c.Foxp3.GFP mice were either unstimulated or stimulated with SEA in the presence of monensin for 6 hours. IL-4 expression was detected by means of intracellular cytokine staining. Dot plots of Treg cells (CD4+GFP+) are shown. C, BALB/c.Foxp3.GFP mice were intravenously injected with either PBS (−SEA) or 2 μg of SEA (+SEA). Six to 7 hours later, splenic cells were stained for cell-surface marker. Dot plots of CD69 and CD62L staining on gated Treg cells (CD4+GFP+) are shown. Numbers in dot plots indicate percentages of cells. Representatives of one of 2 experiments are shown. Journal of Allergy and Clinical Immunology 2017 139, 508-518.e4DOI: (10.1016/j.jaci.2016.04.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Analyses of asthmatic features of OVA-sensitized mice. A, BALB/c mice were intratracheally sensitized with OVA alone or together with SEA and intratracheally challenged with OVA or PBS, as indicated. On day 3 after the last challenge, BALF was collected from the mice. Total BALF cells and percentages of eosinophils and macrophages were determined. Averages and SDs of 3 mice per group of a representative of 3 experiments are shown. B, Histology of H&E-stained lung sections of mice in Fig 3, A. C, PAS staining of lung sections of mice sensitized with OVA or OVA plus SEA and challenged with OVA in Fig 3, A. D, Mice sensitized with OVA or OVA plus SEA were challenged with OVA as above. On day 3 after the last challenge, mice were subjected to bronchial challenge with increasing doses of methacholine. Pulmonary resistance at each dose of methacholine challenge was measured. Averages and SDs of 4 mice per group in 1 of 2 experiments are shown. Journal of Allergy and Clinical Immunology 2017 139, 508-518.e4DOI: (10.1016/j.jaci.2016.04.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Effects of Treg cell transient depletion before sensitization with OVA plus SEA on asthma. A, Wild-type B6 mice or B6.Foxp3DTR mice (FDR) received 2 consecutive daily intraperitoneal injections of DT before the day of sensitization with OVA plus SEA. Mice were challenged with OVA as in Fig 3, A. Total cell numbers and percentages of eosinophils and macrophages in BALF were determined. Averages and SDs of 3 mice per group of a representative of 3 experiments are shown. B, Sections of lungs of the same mice as in Fig 4, A, were subject to H&E or PAS staining. C, Mice treated as in Fig 4, A, were subjected to bronchial methacholine challenge, and pulmonary resistance was measured. Averages and SDs of 4 mice per group in 1 of 2 experiments are shown. Journal of Allergy and Clinical Immunology 2017 139, 508-518.e4DOI: (10.1016/j.jaci.2016.04.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Effects of SEA and Treg cell transient depletion on CDE-induced asthma. A, B6.Foxp3DTR mice were treated with or without 2 consecutive intraperitoneal injection of DT before intratracheal sensitization with CDE alone or plus SEA and challenged with CDE. Total cell numbers and percentages of eosinophils and macrophages in BALF were determined. Averages and SDs of 3 mice per group are shown. B, B6.Foxp3DTR mice sensitized with CDE alone or CDE plus SEA and challenged with CDE as in Fig 5, A, were subjected to bronchial challenge with increasing doses of methacholine. Pulmonary resistance was measured. Averages and SDs of 4 mice per group are shown. Asterisk indicates statistical significance of the difference as determined by the Student t test. Representatives of 2 experiments are shown. Journal of Allergy and Clinical Immunology 2017 139, 508-518.e4DOI: (10.1016/j.jaci.2016.04.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Characterization of early T-cell response to allergen challenge. A, B6.Foxp3DTR mice (FDR) were treated with or without 2 consecutive daily intraperitoneal injections of DT before intratracheal sensitization with OVA and OVA323-339 peptide plus SEA and then intratracheally challenged once with OVA and OVA323-339 peptide for 8 to 9 hours. BALF cells were sequentially stained with phycoerythrin-labeled OVA-2C:IAb and OVA-3C:IAb tetramers and a cocktail of antibodies against surface markers. The cells were then fixed, permeabilized, and stained for IL-13 and IFN-γ. Middle panels are dot plots of CD4 and OVA tetramer staining gated on the TCRβ+ single T cells. Dot plots of IL-13 and IFN-γ staining of the CD4− (left) and CD4+ tetramer-positive (right) cells are shown. B, BALF cells of B6 mice sensitized and challenged with keyhole limpet hemocyanin (KLH) were stained with the OVA tetramers and CD4 as a negative control of tetramer staining. C, MLN cells of the same mice as in Fig 6, A, were treated and analyzed as in Fig 6, A. D, MLN cells of the same mice as in Fig 6, B, as negative controls of tetramer staining of MLN cells. Numbers in all plots are percentages of cell populations. Representatives of 3 experiments are shown. Journal of Allergy and Clinical Immunology 2017 139, 508-518.e4DOI: (10.1016/j.jaci.2016.04.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Restoration of IL-13 expression by Treg cell reconstitution. B6.Foxp3DTR mice (FDR) were treated with 2 consecutive daily intraperitoneal injections of DT before intratracheal sensitization with OVA and OVA323-339 peptide plus SEA. On the day of the second DT injection, mice received either adoptive transfer of Treg cells derived from B6.Foxp3.GFP mice (FDR + DT + Treg) or PBS (FDR + DT). The mice were then sensitized and challenged, and BALF cells were analyzed as in Fig 5. Middle panels are dot plots of CD4 and OVA tetramer staining gated on the TCRβ+ T cells. Dot plots of IL-13 and IFN-γ staining of the CD4− (left) and CD4+ tetramer-positive (right) cells are shown. Numbers in all plots are percentages of the cell populations. Representatives of 2 experiments are shown. Journal of Allergy and Clinical Immunology 2017 139, 508-518.e4DOI: (10.1016/j.jaci.2016.04.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 In vitro TH differentiation of OVA specific CD4 Tcon cells in the absence of SEA. OVA-specific naive CD4 Tcon cells derived from DO11.10.Foxp3.GFP mice were mixed with or without antigen-nonspecific naive Treg cells derived from BALB/c.Thy1.1.Foxp3.GFP mice. Cells were stimulated with APC plus OVA323-339 peptide and IL-12. On day 6 of culture, cells were stimulated with phorbol 12-myristate 13-acetate and ionomycin. IFN-γ and IL-13 levels were measured based on intracellular cytokine staining. Dot plots of CD4+KJ126+GFP− populations are shown. Numbers are percentages of cells in each quadrant. Journal of Allergy and Clinical Immunology 2017 139, 508-518.e4DOI: (10.1016/j.jaci.2016.04.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 BALF cell differential staining. BALB/c mice were intratracheally sensitized with OVA or OVA plus SEA and challenged with either OVA or PBS, as indicated. BALF smear slides were stained with Diff-Quick solutions. Microscopic pictures of the stained slides are shown. Journal of Allergy and Clinical Immunology 2017 139, 508-518.e4DOI: (10.1016/j.jaci.2016.04.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 In vitro TH differentiation of OVA-specific CD4 Tcon cells of OTII.Foxp3.GFP mice. OVA-specific naive CD4 Tcon cells derived from OTII.Foxp3.GFP mice were mixed with or without antigen-nonspecific naive Treg cells derived from B6.Foxp3.GFP mice. Cells were stimulated with APC plus OVA323-339 peptide, SEA, and IL-12. On day 6 of culture, cells were stimulated with phorbol 12-myristate 13-acetate and ionomycin. IFN-γ and IL-13 levels were measured by means of intracellular cytokine staining. Dot plots of the OTII CD4 Tcon cells (CD4+TCRVβ5+) are shown. Numbers are percentages of cells in each quadrant. Journal of Allergy and Clinical Immunology 2017 139, 508-518.e4DOI: (10.1016/j.jaci.2016.04.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Effects of Treg cell deletion after sensitization and before allergen challenge on asthma. B6.FoxpDTR mice were intratracheally sensitized with OVA or OVA plus SEA for 1 week. Before intratracheal challenge with OVA, mice were intraperitoneally injected with or without DT to deplete Treg cells. Mice were then intratracheally challenged 3 times with OVA. BALF from the mice were collected. Total numbers of cells and percentages of eosinophils, macrophages, and lymphocytes in BALF are shown. Journal of Allergy and Clinical Immunology 2017 139, 508-518.e4DOI: (10.1016/j.jaci.2016.04.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions