Antigen-specific effector CD8 T cells regulate allergic responses via IFN-γ and dendritic cell function Yafang Tang, BSc, Shou Ping Guan, BSc, Benson.

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Antigen-specific effector CD8 T cells regulate allergic responses via IFN-γ and dendritic cell function Yafang Tang, BSc, Shou Ping Guan, BSc, Benson Y.L. Chua, BSc, Qian Zhou, BSc, Adrian W.S. Ho, BSc, Kenneth H.S. Wong, BSc, Kok Loon Wong, PhD, W.S. Fred Wong, PhD, David M. Kemeny, PhD, FRCPath Journal of Allergy and Clinical Immunology Volume 129, Issue 6, Pages 1611-1620.e4 (June 2012) DOI: 10.1016/j.jaci.2011.12.976 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Characterization of effector OT-I and IFN-γ−/−OT-I CD8 T cells. CD8 T cells from OT-I and IFN-γ−/−OT-I mice were activated for 48 hours with phorbol 12-myristate 13-acetate and ionomycin. A, Flow cytometric analysis for surface marker expression. B, Transcription factor expression by intracellular staining. C, Cytotoxic profile of naive CD8 T cells determined by 51Cr assay, expressed as percentage of specific lysis of target cells. D, Cytotoxic profile of activated CD8 T cells determined by 51Cr assay, expressed as percentage of specific lysis of target cells. E, Cytokine production in the supernatants measured by ELISA. F, Sensitized mice were adoptively transferred with activated CD8 T cells from either OT-I or IFN-γ−/−OT-I mice before 3 consecutive intranasal challenges. n = 3; ∗P < .05, ∗∗P < .01, ∗∗∗P < .001. in, Intranasally; ip, intraperitoneally; iv, intravenously; MFI, mean fluorescence intensity. Journal of Allergy and Clinical Immunology 2012 129, 1611-1620.e4DOI: (10.1016/j.jaci.2011.12.976) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Recruitment of OVA-specific CD8 T cells in the lung parenchyma in response to CD8 T-cell transfer. 3 × 106 effector OT-I or IFN-γ−/−OT-I CD8 T cells were transferred to OVA-sensitized mice as described in Fig 1, F. A, OVA-specific CD8 T cells in the lung identified by fluorescent-labeled SIINFEKL tetramer. B, Quantitative analysis of OVA-specific CD8 T cells in the lung. C, In vitro proliferation of CD8 T cell after 64-hour phorbol 12-myristate 13-acetate and ionomycin activation. D, In vivo proliferation of CD8 T cells that were labeled prior to adoptive transfer. n = 10; +P < .05 (compared with PBS/PBS mice) and ∗∗P < .01 (compared with OVA/OVA mice). MFI, Mean fluorescence intensity. Journal of Allergy and Clinical Immunology 2012 129, 1611-1620.e4DOI: (10.1016/j.jaci.2011.12.976) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Effect on BAL cytokine production in response to CD8 T-cell transfer. Sensitized mice were adoptively transferred with CD8 T cells and challenged 3 times before sacrifice. Cytokine levels in the BAL fluid were measured by ELISA. n = 10; +P < .05, +++P < .001 (compared with PBS/PBS mice), ∗∗∗P < .001 (compared with OVA/OVA mice). Journal of Allergy and Clinical Immunology 2012 129, 1611-1620.e4DOI: (10.1016/j.jaci.2011.12.976) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Altered cell infiltration in the airway in response to CD8 T-cell transfer. Sensitized mice were adoptively transferred with CD8 T cells and challenged 3 times before sacrifice. A, Representative fluorescence-activated cell sorting plots shown for the percentages of eosinophils (upper panel) and neutrophils (lower panel). B, Quantitative analysis of BAL cells, both in percentage (left) and in total cell number (right). n = 10; ++P < .01 (compared with PBS/PBS mice), ∗P < .05, ∗∗P < .01 (compared with OVA/OVA mice). Eos, Eosinophils; Lym, lymphocytes; Mac, macrophages; Neu, neutrophils. Journal of Allergy and Clinical Immunology 2012 129, 1611-1620.e4DOI: (10.1016/j.jaci.2011.12.976) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Effect on mucus production and lung function in response to CD8 T-cell transfer. Sensitized mice were adoptively transferred with CD8 T cells and challenged 3 times before sacrifice. A, Periodic acid staining (PAS) of lung tissue sections. n = 3. B, Airway resistance in response to increasing concentrations of nebulized methacholine (0.5-8.0 mg/mL). Results were expressed as percentages of respective basal values in response to PBS. n = 6; ++P < .01 (compared with control) and ∗P < .05 (compared with OVA/OVA mice). Journal of Allergy and Clinical Immunology 2012 129, 1611-1620.e4DOI: (10.1016/j.jaci.2011.12.976) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Role of non–antigen-specific CD8 T cells on allergic responses. Sensitized mice were adoptively transferred with CD8 T cells and challenged 3 times before sacrifice. A, Recruitment of non–antigen-specific CD8 T cells (CD45.1+CD45.2− cells) into the lung. B, Quantitative analysis of cell infiltration in the BAL fluid. n = 3; +P < .05, ++P < .01, +++P < 0.001 (compared with PBS/PBS mice), ∗P < .05, ∗∗P < .01, ∗∗∗P < .001 (compared with OVA/OVA mice). Eos, Eosophinils; lym, lymphocytes; mac, macrophages; ND, not detectable; neu, neutrophils; WT, wild type. Journal of Allergy and Clinical Immunology 2012 129, 1611-1620.e4DOI: (10.1016/j.jaci.2011.12.976) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Effect of lung parenchymal DCs on CD4 T-cell priming. Sensitized mice were adoptively transferred with CD8 T cells and challenged 3 times before sacrifice. A, Numbers of different antigen-presenting cells in the lung parenchyma. B, Production of IFN-γ by naive OT-II CD4 T cells after coculture with sorted lung CD11b+CD103− DCs from different treatment groups. C, Production of IFN-γ by lung parenchymal CD4 T cells isolated from respectively treated mice after coculture with sorted lung CD11b+CD103− DCs correspondingly. D, Production of IFN-γ by naive OT-II CD4 T cells after coculture with sorted lung CD11b−CD103+ DCs from different treatment groups. E, Production of IFN-γ by lung parenchymal CD4 T cells isolated from respectively treated mice after coculture with sorted lung CD11b−CD103+ DCs correspondingly. n = 3; +P <.05, ∗P < .05, ∗∗P < .01, ∗∗∗P < .001 (compared with OVA/OVA mice). Mac, Macrophages. Journal of Allergy and Clinical Immunology 2012 129, 1611-1620.e4DOI: (10.1016/j.jaci.2011.12.976) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 8 Infiltration of cells into the airway following adoptive transfer of CD8 T cells in nonimmunized mice. Naive mice were adoptively transferred with activated CD8 T cells followed by 3 intranasal challenges. Mice were sacrificed 1 day after the last challenge. A, Percentage of OVA-specific CD8 T cells in the lung, stained with SIINFEKL tetramer. B, Quantitative analysis of cell infiltration in the BAL fluid. n = 3; +P < .05, ++P < .01 (compared with PBS control) and ∗P < .05, ∗∗P < .01 (compared with PBS/OT-I/OVA mice). Eos, Eosophinils; lym, lymphocytes; mac, macrophages; neu, neutrophils. Journal of Allergy and Clinical Immunology 2012 129, 1611-1620.e4DOI: (10.1016/j.jaci.2011.12.976) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Degranulation of CD8 T cells detected by the accumulation of CD107α. Freshly isolated OT-I or IFN-γ−/−OT-I CD8 T cells were cocultured with target cells EL4 murine lymphoblast cells for 6 hours in the presence of brefeldin A, monesin, and CD107α. Result was expressed as the percentage of CD107α+ CD8 T cells. n = 4; ∗∗P < .01. Journal of Allergy and Clinical Immunology 2012 129, 1611-1620.e4DOI: (10.1016/j.jaci.2011.12.976) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Effect of IFN-γ neutralization on CD8 T-cell–induced suppression of TH2 responses. Sensitized mice were treated with α-IFN-γ antibody via intratracheal transfer before the adoptive transfer of activated OT-I CD8 T cells. Mice were then challenged with OVA for 3 consecutive days. A, Quantitative analysis of cell infiltration in the BAL fluid. B, Periodic acid staining (PAS) of lung tissue sections and statistical analysis. C, Production of IFN-γ by naive OT-II CD4 T cells after coculture with sorted lung CD11b+CD103− DCs from different treatment groups. D, Production of IFN-γ by lung parenchymal CD4 T cells isolated from respectively treated mice after coculture with sorted lung CD11b+CD103− DCs correspondingly. E, Production of IFN-γ by naive OT-II CD4 T cells after coculture with sorted lung CD11b−CD103+ DCs from different treatment groups. F, Production of IFN-γ by lung parenchymal CD4 T cells isolated from respectively treated mice after coculture with sorted lung CD11b−CD103+ DCs correspondingly. +++P < .001 (compared with PBS/PBS mice). ∗P < .05, ∗∗P < .01, ∗∗∗P < .001 (compared with OVA/OVA mice). Eos, Eosophinils; lym, lymphocytes; mac, macrophages; neu, neutrophils. Journal of Allergy and Clinical Immunology 2012 129, 1611-1620.e4DOI: (10.1016/j.jaci.2011.12.976) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Effect of IFN-γ neutralization and number of CD8 T cells on cell infiltration into the airway following OT-I CD8 T-cell transfer and challenges in nonimmunized mice. Naive mice were adoptively transferred with different numbers of activated OT-I CD8 T cells followed by 3 intranasal challenges. Mice were sacrificed 1 day after the last challenge. A, Percentage of OVA-specific CD8 T cells in the lung, stained with SIINFEKL tetramer. B, Quantitative analysis of cell infiltration in the BAL fluid. For IFN-γ neutralization, α-IFN-γ antibody was given to mice right before the transfer of 3 × 106 CD8 T cells. C, Percentage of OVA-specific CD8 T cells in the lung, stained with SIINFEKL tetramer. D, Quantitative analysis of cell infiltration in the BAL fluid. n = 3; +P < .05, ++P < .01, +++P < .001 (compared with PBS/PBS mice). Eos, Eosophinils; lym, lymphocytes; mac, macrophages; neu, neutrophils. Journal of Allergy and Clinical Immunology 2012 129, 1611-1620.e4DOI: (10.1016/j.jaci.2011.12.976) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions