Rescue of T-cell function during persistent pulmonary adenoviral infection by Toll-like receptor 9 activation Tristan Holland, PhD, Dirk Wohlleber, PhD,

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Rescue of T-cell function during persistent pulmonary adenoviral infection by Toll-like receptor 9 activation Tristan Holland, PhD, Dirk Wohlleber, PhD, Samira Marx, MSc, Thomas Kreutzberg, PhD, Salvador Vento-Asturias, BSc, Christine Schmitt-Mbamunyo, BTA, Meike Welz, MSc, Marianne Janas, PhD, Karl Komander, MSc, Sarah Eickhoff, MSc, Anna Brewitz, PhD, Mike Hasenberg, PhD, Linda Männ, PhD, Matthias Gunzer, PhD, Christoph Wilhelm, PhD, Wolfgang Kastenmüller, MD, Percy Knolle, MD, Zeinab Abdullah, PhD, Christian Kurts, MD, Natalio Garbi, PhD Journal of Allergy and Clinical Immunology Volume 141, Issue 1, Pages 416-419.e10 (January 2018) DOI: 10.1016/j.jaci.2017.06.048 Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Persistent pulmonary infection in mice with adenovirus results in CD8 T-cell functional impairment. A, Bioluminescence images of B6 albino mice intratracheally infected with the indicated AdLGO doses. B, Bioluminescence kinetics in the thoraxes of AdLGO-infected mice. C, Bioluminescence images of B6 albino mice infected intratracheally with 5 × 108 AdLGO infections units up to 100 dpi. D, Bioluminescence kinetics in the thoraxes of AdLGO-infected mice up to 100 dpi. E, Confocal immunofluorescence of lungs infected 28 or 100 days earlier with tdT-expressing AdLTO or AdLacZ as a negative control. Infected cells (tdT+) are shown in red. Arrowheads, tdT+ epithelial cells. Bar = 100 μm. F, Naive or AdLGO chronically infected mice received CFSE-labeled naive OT-I cells, and some mice were also challenged with intratracheal OVA. Shown are dot plots indicating the percentage of GzmB+ cells among OT-I CD8 T cells in the mediastinal lymph nodes and corresponding quantification (right panel) 3 days after transfer. G, As in Fig 1, D, except that mice received P14 CD8 T cells and were challenged intratracheally with LCMVGP33-41 antigen. Dot plots show GzmB expression by P14 cells. AdLGO, Adenovirus encoding for luciferase, eGFP, and OVA; AdLTO, adenovirus encoding for luciferase, tdT, and OVA; if.u., infection units; i.t., intratracheal. Shown is a representative of 3 independent experiments (n = 4 mice per group). *P < .05, ANOVA (Fig 1, F) or the Student t test (Fig 1, G). Journal of Allergy and Clinical Immunology 2018 141, 416-419.e10DOI: (10.1016/j.jaci.2017.06.048) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Local CpG instillation results in functional recovery of virus-specific CD8 T cells and clearance of persistent adenoviral infection. A, Bioluminescence signal in the thoraxes of chronic AdLGO mice undergoing PBS or CpG treatment (arrows). Mice had been infected with 5 × 108 infection units on day 0. i.t., Intratracheal; i.v., intravenous. B, As in Fig 2, A, but some mice received CD8 T cell–depleting antibody (arrowheads). C, Percentages (dot plots) and numbers (right panel) of virus-specific CD8 T cells in the lung of mice treated or not with CpG intratracheally as in Fig 2, A. Dex, Kb/SIINFEKL dextramer. D, Proliferation of virus-specific CD8 T cells in mediastinal lymph nodes from AdLGO-infected mice and treated as in Fig 2, A. E-H, Apoptotic rate (Fig 2, E), GzmB expression (Fig 2, F), glucose uptake (Fig 2, G), and mitochondrial membrane potential (Fig 2, H) of pulmonary AdLGO-specific CD8 T cells after intratracheal CpG or PBS treatment, as in Fig 2, A. Shown is a representative of at least 3 independent experiments (n = 4-5 mice per group). *P < .05, **P < .01, and ***P < .001, Student t test (Fig 2, A-H; Fig 2, A, against intravenous CpG; Fig 2, B, against anti-CD8α) or ANOVA (Fig 2, F). Journal of Allergy and Clinical Immunology 2018 141, 416-419.e10DOI: (10.1016/j.jaci.2017.06.048) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Pulmonary epithelial cells constitute the main cellular compartment infected with adenovirus during the chronic phase. Representative contour plots showing the percentage of infected cells (tdT+) in lungs of mice instilled 28 days earlier with 5 × 108 infection units of intratracheal tdT-expressing AdLTO or AdlacZ as a negative control. Gating was done as follows: epithelial cells (EpC; CD326+CD31−CD45.2−Ter119−), endothelial cells (EnC; CD326−CD31+CD45.2−Ter119−), other stromal cells (O.S.; CD326−CD31−CD45.2−Ter119−), AMs (Siglec-F+CD11c+CD45.2+), non-AM leukocytes (Siglec-F−CD45.2+), interstitial macrophages (iM; Siglec-F−CD45.2+CD11c−CD11b+F4/80+), and dendritic cells (Siglec-F−CD45.2+CD11c+I-A/I-E+). All events were pregated on live cells. Bar graphs show quantification of data in the contour. MFI, Mean fluorescence intensity. Shown is a representative of 3 independent experiments. ***P < .001, ANOVA. Journal of Allergy and Clinical Immunology 2018 141, 416-419.e10DOI: (10.1016/j.jaci.2017.06.048) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Body weight progression in mice undergoing pulmonary adenoviral infection. if.u., Infection units; i.t., intratracheal. Journal of Allergy and Clinical Immunology 2018 141, 416-419.e10DOI: (10.1016/j.jaci.2017.06.048) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Adenovirus-specific CD8 T cells are generated during the acute phase of infection. A, B6 mice were infected intratracheally with 5 × 108 AdLGO infection units (if.u.) intratracheally and the frequency and number of Kb/SIINFEKL-specific CD8 T cells identified by dextramer staining in the indicated samples. Flow cytometric density contours were pregated on live CD8 T cells. Dex, Dextramer; Kb/S8L+, Kb/SIINFEKL-Dex+; mLN, Lung-draining mediastinal lymph nodes; N.D., Not detected (CD8 T cells are not present in the bronchoalveolar space of naive mice). B, Frequency of total CD8 T cells in indicated samples of naive and AdLGO infected mice as in Fig E3, A. Shown is a representative of at least 3 independent experiments. Journal of Allergy and Clinical Immunology 2018 141, 416-419.e10DOI: (10.1016/j.jaci.2017.06.048) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Adenovirus-specific CD8 T cells do not upregulate effector molecules and mechanisms during adenoviral persistence. AdLGO infection, OVA challenge intratracheally and adoptive transfer of CD45.1+ CFSE-labeled AdLGO-specific naive OT-I T cells were performed as in Fig 1, F. Analysis of CD25 (A), IFN-γ (B), and TNF-α (C) expression, as well as degranulation activity (D) by OT-I CD8 T cells in the mediastinal lymph nodes was performed 3 days after transfer. Shown is a representative of 3 independent experiments (n = 4 mice per group). *P < .05, **P < .01, and ***P < .001, ANOVA (n = 4 mice per group). Journal of Allergy and Clinical Immunology 2018 141, 416-419.e10DOI: (10.1016/j.jaci.2017.06.048) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 CpG instillation intratracheally promotes expression of proinflammatory cytokines in the lungs of mice with AdLGO persistent infection. Quantification of cytokine content in the BAL fluid of mice infected or not with 5 × 108 AdLGO infection units intratracheally is shown. A, Mice were treated at 38 dpi with PBS or 5 μg of CpG intratracheally, and the BAL fluid was collected 48 hours later. B, Naive mice infected with 5 × 108 AdLGO infection units 7 days earlier or 40 days earlier and treated with PBS or 5 μg of CpG intratracheally 30, 33, and 38 dpi. BAL fluid was collected 48 hours later. Shown is a representative of 2 independent experiments (n = 4 mice per group). *P < .05, **P < .01, and ***P < .001, ANOVA. Journal of Allergy and Clinical Immunology 2018 141, 416-419.e10DOI: (10.1016/j.jaci.2017.06.048) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 Enhanced virus-specific CTL proliferation after local CpG instillation in AdLGO persistently infected mice. Histograms (left panels) showing percentages of proliferating CD44hiKb/S8L-Dex+ CTLs in chronically infected mice recovered from the lungs or mediastinal lymph nodes (mLN). AdLGO, Infected with 5 × 108 infection units of AdLGO 40 days earlier and treated with PBS intratracheally at 30, 33, and 38 dpi; AdLGO + CpG, similarly infected and treated with 5 μg of CpG intratracheally. Right panel, Respective cumulative analysis for Dex+ and Dex−CD44hi CD8 T cells, as indicated. Dex, Kb/SIINFEKL dextramer; if.u., infection units; i.t., intratracheal. Shown is a representative of 3 independent experiments (n = 4 mice per group). **P < .01 and ***P < .001, Student t test. Journal of Allergy and Clinical Immunology 2018 141, 416-419.e10DOI: (10.1016/j.jaci.2017.06.048) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E7 Expression of inhibitory receptors on virus-specific CD8 T cells during adenoviral persistence. A and B, Expression of Tim-3, cytotoxic T lymphocyte–associated antigen 4 (CTLA4), and CD160 (Fig E7, A) and PD-1 (Fig E7, B) on Kb/SINNFEKL dextramer-positive (Dex+) CD8 T cells in the lungs of infected mice having received or not 5 μg of CpG administered intratracheally as in Fig 2, A. C, Mice were infected with 5 × 108 AdLGO infection units (if.u.) intratracheally and treated with anti−PD-L1 antibodies intraperitoneally, when indicated (arrows). Iso, Isotype control. Shown is a representative of 2 experiments using 5 mice per group. ***P < .001, Student t test. Journal of Allergy and Clinical Immunology 2018 141, 416-419.e10DOI: (10.1016/j.jaci.2017.06.048) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E8 CpG treatment leads to potent cytolytic activity of virus-specific CTLs in the airways. Ex vivo Kb/SIINFEKL-specific cytotoxic activity against splenocyte target cells by CTLs isolated from the BAL fluid of either mice infected with 5 × 108 infection units AdLGO 40 days earlier and treated with CpG intratracheally at 30, 33, and 38 dpi or mice infected with 5 × 108 infection units of AdLGO 7 days earlier. E, Kb/SIINFEKL-specific CTLs; T, Kb/SIINFEKL-loaded splenocyte targets. *P < .05; **P < .01, Student t test. Journal of Allergy and Clinical Immunology 2018 141, 416-419.e10DOI: (10.1016/j.jaci.2017.06.048) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions