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TIGIT Enhances Antigen-Specific Th2 Recall Responses and Allergic Disease Evangelia Kourepini, Nikolaos Paschalidis, Davina C

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TIGIT Enhances Antigen-Specific Th2 Recall Responses and Allergic Disease Evangelia Kourepini, Nikolaos Paschalidis, Davina C TIGIT Enhances Antigen-Specific Th2 Recall Responses and Allergic Disease Evangelia Kourepini, Nikolaos Paschalidis, Davina C. M. Simoes, Maria Aggelakopoulou, Jane L. Grogan and Vily This information is current as Panoutsakopoulou of October 2, 2021. J Immunol 2016; 196:3570-3580; Prepublished online 25 March 2016; doi: 10.4049/jimmunol.1501591 http://www.jimmunol.org/content/196/9/3570 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2016/03/24/jimmunol.150159 Material 1.DCSupplemental References This article cites 45 articles, 18 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/196/9/3570.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 2, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology TIGIT Enhances Antigen-Specific Th2 Recall Responses and Allergic Disease Evangelia Kourepini,* Nikolaos Paschalidis,* Davina C. M. Simoes,* Maria Aggelakopoulou,* Jane L. Grogan,† and Vily Panoutsakopoulou* T cell Ig and ITIM domain receptor (TIGIT), expressed on T, NK, and regulatory T cells, is known as an inhibitory molecule that limits autoimmunity, antiviral and antitumor immunity. In this report, we demonstrate that TIGIT enhances Th2 immunity. TIGIT expression was upregulated in activated Th2 cells from mice with experimental allergic disease and in Th2 polarization cultures. In addition, its high-affinity ligand CD155 was upregulated in mediastinal lymph node dendritic cells from allergic mice. In an in vitro setting, we observed that Tigit expression in Th2 cells and its interaction with CD155 expressed in dendritic cells were important during the development of Th2 responses. In addition, blockade of TIGIT inhibited Th2, but had no effect on either Th1 or Th17 polarization. In vivo blockade of TIGIT suppressed hallmarks of allergic airway disease, such as lung Downloaded from eosinophilia, goblet cell hyperplasia, Ag-specific Th2 responses, and IgE production, and reduced numbers of T follicular helper and effector Th2 cells. Thus, TIGIT is critical for Th2 immunity and can be used as a therapeutic target, especially in light of recent findings showing TIGIT locus hypomethylation in T cells from pediatric patients with allergic asthma. The Journal of Immunology, 2016, 196: 3570–3580. cell Ig and ITIM domain receptor (TIGIT), also known as allergic Th2 type responses remain unknown. Therefore, we WUCAM (1) or Vstm3 (2, 3), has been described as an addressed the role of TIGIT in Th2 immunity and specifically in http://www.jimmunol.org/ T inhibitory molecule expressed on memory T, activated T, Th2 recall responses that lead to allergic asthma. NK and regulatory T (Treg) cells (4–6). TIGIT has been found to A recent study demonstrated that the TIGIT locus is hypo- limit autoimmunity (2, 7) and to restrain T cell responses acting as methylated, and its gene product is overexpressed in CD4+ T cells an intrinsic inhibitory molecule by decreasing TCR activation, of pediatric patients with allergic asthma (14). In another study, proliferation, and cytokine secretion (5, 7). TIGIT expressed on T splenocytes of immunized Cd1552/2 mice secreted lower levels of or NK cells can bind to its high-affinity ligand CD155 (1), also IL-4 and contained fewer IL-4– and GATA-3–expressing CD4+ known as poliovirus receptor (8) or Necl-5 (9), expressed on the T cells (15). Of note, a recent report showed that TIGIT-expressing + surface of APCs (4, 10, 11). Engagement of TIGIT to CD155 Foxp3 T cells could not suppress allergic asthma upon transfer by guest on October 2, 2021 promotes IL-10 while it restrains IL-12 production by dendritic (6). The above findings suggest that TIGIT may play a role in Th2 cells (DCs), leading to reduced T cell activation in vitro (4). immunity, possibly distinct from its role in other types of immu- + TIGIT-expressing Foxp3 T cells have been recently characterized nity. In this report, we provide evidence that TIGIT expression by as a highly functional Treg cell subset that selectively suppresses Th cells and its interaction with CD155 enhances Th2 responses, Th1 and Th17 responses (6). In addition, upregulated TIGIT ex- and blockade of TIGIT is therapeutic for experimental allergic + pression by tumor-infiltrating CD8 T cells promotes T cell ex- airway inflammation. haustion and tumor expansion (12, 13). Likewise, high TIGIT + expression by CD8 T cells inhibits antiviral immunity (12). Al- Materials and Methods though TIGIT expression by T cells has suppressive effects on Mice autoimmunity, antiviral, and antitumor immunity, its effects on BALB/c and OVA-specific TCR-transgenic DO11.10 (Tcr-TG-DO11.10) mice were purchased from The Jackson Laboratory (Bar Harbor, ME). *Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Mice were housed at the Animal Facility of the Biomedical Research Foundation of the Academy of Athens, Athens 115 27, Greece; and †Department of Foundation of the Academy of Athens. Protocols were approved by the Cancer Immunology, Genentech, South San Francisco, CA 94080 Bioethics Committee of Biomedical Research Foundation of the Academy ORCIDs: 0000-0002-2299-1007 (E.K.); 0000-0002-1569-1508 (V.P.). of Athens and the Greek Government. All procedures were in accordance with the National Institutes of Health Statement of Compliance (Assur- Received for publication July 17, 2015. Accepted for publication February 23, 2016. ance) with Standards for Humane Care and Use of Laboratory Animals This work was supported by the European Research Council (ERC) under the Eu- (A5736-01) and with the European Union Directive 86/609/EEC for the ropean Union’s Seventh Framework Programme (FP/2007–2013)/ERC Grant Agree- protection of animals used for experimental purposes. ment 243322 (to V.P.) and by the Greek General Secretariat of Research and Technology Grant Aristeia I 2618 (to V.P.). In vivo experimental protocols Address correspondence and reprint requests to Dr. Vily Panoutsakopoulou, Biomed- ical Research Foundation of the Academy of Athens, 4 Soranou Efessiou Street, Mice were immunized with 0.01 mg chicken OVA (Sigma-Aldrich) in 0.2 Athens 115 27, Greece. E-mail address: [email protected] ml aluminum hydroxide (alum; Serva) i.p. on days 0 and 12. After the two The online version of this article contains supplemental material. immunizations (on day 18), draining lymph nodes (LNs) of DO11.10 mice were isolated, and CD4+CD44hiCD62L+CD127+ T memory cells were Abbreviations used in this article: alum, aluminum hydroxide; BAL, bronchoalveolar sorted for cocultures with naive DCs. For allergic airway disease induction lavage; DC, dendritic cell; LN, lymph node; MLN, mediastinal lymph node; PAS, periodic acid–Schiff; PD-1, programmed cell death-1; Tfh, T follicular helper; after OVA/alum immunizations, BALB/c mice were administered aero- TIGIT, T cell Ig and ITIM domain receptor; Treg, regulatory T. solized OVA (5%, for 20 min) three times on days 18–20. Each mouse received 20 mg affinity-purified blocking polyclonal Ab against TIGIT Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 (AF-7267, R&D Systems) or corresponding Ig isotype control Ab (R&D www.jimmunol.org/cgi/doi/10.4049/jimmunol.1501591 The Journal of Immunology 3571 Systems) three times i.p., 2 h before challenges. Similarly, we used 20 mg/ Quantitative PCR mouse purified monoclonal blocking Abs against TIGIT (1G9), CD155 RNA extraction, quantification, and cDNA synthesis from isolated DCs or (4.24.1-LEAF), or isotype control Ig Abs (MOPC-21 and RTK2758- + LEAF; BioLegend). For certain experiments, we administered 250 mg/ CD4 T cells were performed as previously described (20). Primers were mouse monoclonal IgG2a blocking Ab against TIGIT (clone 10A7) (4, designed using the Primer 3 program and are as follows: Tigit sense primer, 12), kindly provided by Genentech, or the corresponding Ig isotype control 59-GTGGGATTTACAAGGGGAGA-39 and antisense, 59-CTTCCAGGG- Ab (R&D Systems). Mice were euthanized on day 21. We stained paraffin- GATGAGAGAC-39; Gata3 sense primer, 59-TTACCACCTATCCGCCC- embedded lung sections (4 mm) with H&E and periodic acid–Schiff (PAS) TAT-39 and antisense, 59-ACACACTCCCTGCCTTCTG-39; Cd226 sense to evaluate lung infiltration and goblet cell hyperplasia, as previously de- primer, 59-CAAGAACACTGGCACAAAGA-39 and antisense, 59-GAAA- scribed (16). We used a semiquantitative scoring system to grade the size CAAGCAGGAGTAGATGC-39; c-maf sense primer, 59-CCCTTGA- of lung infiltrates as previously described (17). Goblet cells were counted CAGTTTGCTTCTA-39 and antisense, 59-CCCATTCTGCTATCTTTGAC-39; on PAS-stained lung sections using an arbitrary scoring system as de- Rorc sense primer, 59-TGTTTTATGGGGTTTGGGTA-39 and antisense, scribed previously (17). Images from H&E and PAS stained sections were 59-AAGAGATTGTGTGCCAGAG-39;andTbx21 sense primer, 59- obtained by a Leica DM LS2 optical microscope and analyzed with Leica TAGTGATTGGTTGGAGAGGA-39 and antisense, 59-GTAGTTCGGGCA- Application Suite V3.6.0 (Leica Microsystems). We harvested, measured, GAGAAAG-39 (Eurofins MWG). Primers for Cd155 were previously de- and analyzed bronchoalveolar lavage (BAL) inflammatory cells, as pre- scribed (15). Real-time PCR was performed as previously described (20). viously described (16, 17). Serum Ab concentration of OVA-specific IgE was measured with an ELISA kit (BioLegend).
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