TH17 cells mediate pulmonary collateral priming

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TH17 cells mediate pulmonary collateral priming Melanie Albrecht, PhD, Hui-Chen Chen, PhD, Paula Preston-Hurlburt, Patricia Ranney, Heinz-Gerd Hoymann, PhD, Joachim Maxeiner, PhD, Valérie Staudt, MS, Christian Taube, MD, H. Kim Bottomly, PhD, Anna-Maria Dittrich, MD Journal of Allergy and Clinical Immunology Volume 128, Issue 1, Pages 168-177.e8 (July 2011) DOI: 10.1016/j.jaci.2011.01.067 Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Protocol and phenotype of TH1 collateral priming. A, Collateral priming protocol. i.n., Intranasal; i.v., intravenous. B, BAL pattern of TH1 versus TH2 (transfer) collateral priming, with OVA and KLH (O+K) applied during the first and OVA (O) or KLH (K) applied during the second challenge phase. C, KLH-specific serum IgG2a levels in TH1 collateral priming (representative experiments; n = 3-5 animals per group). Experiments were performed 3 to 7 times. ∗P < .05. Journal of Allergy and Clinical Immunology 2011 128, 168-177.e8DOI: (10.1016/j.jaci.2011.01.067) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Cytokine profiles of TH1 collateral priming and independence from IFN-γ. A, Cytokine profiles of in vitro polarized TH1 (white) and TH2 (black) cells (duplicates). The experiment was performed 17 times. B, LN cultures obtained at day 4 of TH1 collateral priming (black, IFN-γ; gray, IL-5; white, IL-13; mean values of duplicates, experiment performed 5 times). n.d., Not detectable. C and D, BAL cells from mice undergoing the TH1 collateral priming protocol receiving IFN-γ–neutralizing antibody or isotype (treatment; Fig 2, C) or mice being deficient for IFN-γ receptor versus wild-type mice (acceptor; Fig 2, D). B, BSA; 1st, first challenge; ns, not significant; O, OVA; 2nd, second challenge. Experiments were performed 3 to 4 times. Journal of Allergy and Clinical Immunology 2011 128, 168-177.e8DOI: (10.1016/j.jaci.2011.01.067) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Role of IL-17A in TH1 collateral priming. A and B, Intracellular cytokine analysis (Fig 3, A) and supernatant ELISA levels (Fig 3, B) of IL-17A and IFN-γ production from in vitro polarized TH1 cells (gray, IFN-γ; black, IL-17A). C, Multiplex analysis of IL-17A production as in Fig 2, B. n.d., Not detectable (duplicates). D and E, BAL cells and KLH-specific serum IgG2a levels from mice undergoing the TH1 collateral priming protocol receiving IL-17A–neutralizing antibody (treatment). 1st, First challenge; K, KLH; O, OVA; 2nd, second challenge. n = 5 animals per group. ∗P < .05. ∗∗∗P < .001. Experiments were performed 3 to 5 times. Journal of Allergy and Clinical Immunology 2011 128, 168-177.e8DOI: (10.1016/j.jaci.2011.01.067) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 TH17 cells mediated collateral priming. BAL differential (A), lung hematoxylin and eosin staining (B), KLH-specific serum IgG2a levels (C), and invasive lung function measurements (D) of mice subjected to TH17 collateral priming. Control mice received either no cells or only KLH (K) in the first (1st) and second (2nd) challenge phases. Fig 4, B: magnification ×100x. Fig 4, D: Bars represent the effective inhalational dose (ED150) of methacholine in micrograms eliciting a 150% increase in lung resistance (RL) compared with baseline. Fig 4, D: n = 9-10 (∗P < .05, unpaired Student t test). Fig 4, A and C: n = 3-10 (∗P < .05, ∗∗P < .01, and ∗∗∗P < .001). ns, Not significant; O, OVA. Experiments were performed 8 times. Journal of Allergy and Clinical Immunology 2011 128, 168-177.e8DOI: (10.1016/j.jaci.2011.01.067) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Phenotype of endogenous TH17 cells. A and B, Intracellular cytokine staining (Fig 5, A) and ELISA supernatant analysis (Fig 5, B) for IL-17A and IFN-γ secretion from CD4+ cells of lung/LN cultures from control mice (nil/O+K/O) and mice subjected to collateral priming (Th17/O+K/K). C and D, CD44 and CD62L surface expression (Fig 5, C) and CD62L mean fluorescence intensity (MFI; Fig 5, D) of CD62Lhigh and CD62Linter-low populations of CD4+ lung cells producing IFN-γ or IL-17A obtained from lungs of mice subjected to TH17 collateral priming. Experiments were performed 3 to 6 times. n.d., Not detected. Fig 5, A and C: For gating strategy, see Fig E5 in this article’s Online Repository. Journal of Allergy and Clinical Immunology 2011 128, 168-177.e8DOI: (10.1016/j.jaci.2011.01.067) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Memory response and control groups for TH1 collateral priming Memory response and control groups for TH1 collateral priming. A, BAL cell numbers of mice that underwent TH1 collateral priming. Mice received TH1-polarized cells and were consecutively challenged with OVA and BSA (O+B) or BSA alone (B) during the first challenge phase and analyzed after the second challenge phase with either BSA (B) or OVA (O) or after a third challenge phase 8 weeks later. B, Comparison of BAL cell numbers from different control mice that were subjected to the collateral priming protocol. naive, Transfer of naive (not polarized) transgenic T cells; ns, not significant; PBS, mice received buffer in the first challenge phase (n = 5 animals per group). Experiments were performed 2 to 3 times. ∗∗P > .01. Journal of Allergy and Clinical Immunology 2011 128, 168-177.e8DOI: (10.1016/j.jaci.2011.01.067) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Invasive lung function after TH17 collateral pulmonary priming Invasive lung function after TH17 collateral pulmonary priming. ED100 (A), ED200 (B), and dose-response curve (C) values of mice undergoing TH17 collateral pulmonary priming. 1st, first challenge with OVA and KLH (O+K); 2nd, second challenge with OVA (O) or KLH (K); transfer, TH17 cells or buffer. Fig E2, A and B: Bars represent the effective inhalational dose (ED100 and ED200) of methacholine (MCh) in micrograms calculated from the individual dose-response curves eliciting a 100% or 200% increase in lung resistance (RL) compared with baseline. Fig E2, C: Dose-response curve (methacholine vs lung resistance) of the same mice. Because of the experimental protocol (animals are not provoked further with methacholine once they reach maximal bronchoconstriction, as evidenced by no further increase of bronchoconstriction with higher methacholine doses), the animal number decreases with increasing methacholine dosages. Fig E2, A and B: n = 8-10. Fig E8, C: n as depicted in graph. ∗P < .05 and ∗∗P < .01, unpaired t test for Th17/O+K/O or Th17/O+K/K versus negative control (nil/O+K/K). The experiment was performed once. Journal of Allergy and Clinical Immunology 2011 128, 168-177.e8DOI: (10.1016/j.jaci.2011.01.067) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Absence of transferred transgenic T cells after collateral priming protocol. Expression of CD4 and transgenic OVA-specific T-cell receptor (KJ1-26+) by IL-17A– and IFN-γ–producing lung cells after unspecific restimulation from control mice (ie, receiving no cells [nil/O+K/O]) and mice subjected to collateral priming (Th17/O+K/K). Analysis was performed on day 22 of the collateral priming protocol. Lung cells were pooled from each group at the time of death (n = 5 animals per group). The experiment was performed once. For gating strategy, see Fig E5. Journal of Allergy and Clinical Immunology 2011 128, 168-177.e8DOI: (10.1016/j.jaci.2011.01.067) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Increase of CD4+ cell proportion in lungs after TH17 collateral priming. FACS analysis of CD4+ (gray) and CD8+ (white) populations among total lung cells from animals that received TH17 cells compared with control mice (nil). All groups were challenged with OVA and KLH (O+K) during the first challenge phase and either OVA (O) or BSA (B) alone during the second challenge phase. Lung cells were pooled from each group at the time of death (n = 3 animals per group). The experiment was performed once. Journal of Allergy and Clinical Immunology 2011 128, 168-177.e8DOI: (10.1016/j.jaci.2011.01.067) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Gating strategy for intracellular cytokine staining of lung and LN cells. Lymphocytes from lungs or LNs were gated regarding their forward-scatter (FSC) and side-scatter (SSC) properties. CD4+ lymphocytes were analyzed regarding their intracellular IL-17A and IFN-γ expressions. The resulting IL-17A and IFN-γ single-positive populations were further analyzed with regard to CD62L and CD44 surface expression. Experiments were performed 3 times. Journal of Allergy and Clinical Immunology 2011 128, 168-177.e8DOI: (10.1016/j.jaci.2011.01.067) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Comparison of cytokine release from lung and LN cells after specific and unspecific restimulation. ELISA measurements of IL-17A and IFN-γ production by LN and lung cell cultures from control mice (white, nil/O+K/O) and mice subjected to TH17 collateral priming (black, Th17/O+K/K) at day 22. Cells were restimulated at 4 hours with PMA/ionomycin (A, triplicates) or 48 hours with KLH or OVA, respectively, in the presence of bone marrow–derived dendritic cells, with medium serving as a negative control (B, duplicates). Lung and LN cells were pooled from each group at the time of death (n = 5 animals per group). The experiment was performed once. Journal of Allergy and Clinical Immunology 2011 128, 168-177.e8DOI: (10.1016/j.jaci.2011.01.067) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Independence of TH2 collateral priming from IL-17 Independence of TH2 collateral priming from IL-17. BAL differential pattern of collateral priming induced by TH17 versus TH2 cell transfer subjected to anti–IL-17A antibody (αIL-17A) or matching isotype control treatment during cell transfer and the first challenge phase. OVA and KLH (O+K) were applied during the first challenge phase, and KLH (K) was applied during the second challenge phase. Control mice did not receive cells or antibody (nil; n = 4-10 animals per group). The experiment was performed once. ∗∗P > .01. ns, Not significant. Journal of Allergy and Clinical Immunology 2011 128, 168-177.e8DOI: (10.1016/j.jaci.2011.01.067) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Neutrophil influx during the TH17 collateral priming protocol Neutrophil influx during the TH17 collateral priming protocol. Comparison of neutrophil numbers in BAL fluid from mice that underwent the TH17 collateral priming protocol 24 hours after the first (striped), 24 hours after the second (white), and 72 hours after the second (black) challenge phase (n = 3 animals per group). The experiment was performed once. Journal of Allergy and Clinical Immunology 2011 128, 168-177.e8DOI: (10.1016/j.jaci.2011.01.067) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions