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553.Full.Pdf Cutting Edge: DNAX Accessory Molecule 1− Deficient CD8+ T Cells Display Immunological Synapse Defects That Impair Antitumor Immunity This information is current as of October 4, 2021. Kelly M. Ramsbottom, Edwin D. Hawkins, Raz Shimoni, Mairi McGrath, Christopher J. Chan, Sarah M. Russell, Mark J. Smyth and Jane Oliaro J Immunol 2014; 192:553-557; Prepublished online 13 December 2013; Downloaded from doi: 10.4049/jimmunol.1302197 http://www.jimmunol.org/content/192/2/553 Supplementary http://www.jimmunol.org/content/suppl/2013/12/13/jimmunol.130219 http://www.jimmunol.org/ Material 7.DC1 References This article cites 25 articles, 10 of which you can access for free at: http://www.jimmunol.org/content/192/2/553.full#ref-list-1 Why The JI? Submit online. by guest on October 4, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • 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 © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Cutting Edge Immunology Cutting Edge: DNAX Accessory Molecule 1–Deficient CD8+ T Cells Display Immunological Synapse Defects That Impair Antitumor Immunity Kelly M. Ramsbottom,* Edwin D. Hawkins,* Raz Shimoni,† Mairi McGrath,* ,‡ ,†,x ,‡,{ Christopher J.x Chan,* Sarah M. Russell,* Mark J. Smyth,* and Jane Oliaro*, DNAX accessory molecule 1 (DNAM-1) is expressed on receptors. These receptors bind to nectin and nectin-like pro- all CD8+ T cells and promotes their activation and teins, and include DNAX accessory molecule 1 (DNAM-1; effector function. DNAM-1 interacts with LFA-1, a crit- CD226, PTA-1) and others (5). DNAM-1 interacts with the ical molecule for immunological synapse formation be- polarity protein, Discs Large, and the actin binding protein, tween T cells and APCs, and for cytotoxic killing of 4.1G, to mediate cytoskeletal changes important for cell ad- Downloaded from target cells. Mice that lack DNAM-1 display abnormal hesion (6). DNAM-1 also interacts with the integrin LFA-1 T cell responses and antitumor activity; however, the (7–9), an important mediator of stable conjugation and syn- apse formation between T cells and APCs or target cells (10). mechanism involved is unclear. In this article, we show 2/2 that DNAM-1 deficiency results in reduced proliferation Studies using DNAM-1 gene–deficient mice (DNAM-1 ) + have highlighted the importance of DNAM-1 in both pro- of CD8 T cells after Ag presentation and impaired http://www.jimmunol.org/ tection against infectious agents and control of tumor growth. cytotoxic activity. We also demonstrate that DNAM- 2 2 DNAM-1 / mice take longer to clear lymphocytic chorio- 1–deficient T cells show reduced conjugations with tu- meningitis virus infection (11). DNAM-1 expression on NK mor cells and decreased recruitment of both LFA-1 and cells promotes cytotoxic activity against DNAM-1 ligand- 2 2 lipid rafts to the immunological synapse, which corre- expressing tumor cells (5, 12), whereas DNAM-1 / mice lates with reduced tumor cell killing in vitro. This syn- show impaired antitumor responses in vivo (13). DNAM-1 apse defect may explain why DNAM-1–deficient mice ligands are frequently overexpressed by tumor cells (12, 14), cannot clear tumors in vivo, and highlights the impor- and polymorphisms in the DNAM-1 gene are associated with tance of DNAM-1 and the immunological synapse in the development of autoimmune diseases (15, 16). However, by guest on October 4, 2021 T cell–mediated antitumor immunity. The Journal of the mechanism by which DNAM-1 contributes to T cell Immunology, 2014, 192: 553–557. activation remains unclear. DNAM-1 may be involved in direct T cell signaling pathways or the cell–cell interactions + required for optimal T cell activation and effector function. ytotoxic CD8 T cells form an integral part of the + immune response against pathogens (1) and in the We therefore investigated the response of CD8 T cells from immunosurveillance of cancer (2). The activation of DNAM-1–deficient mice to Ag presentation and their inter- C + action with tumor cells in vitro. Our results demonstrate that naive CD8 T cells is dependent on TCR–MHC class I + interactions with APCs, during which sustained contact be- DNAM-1 is required for optimal activation of naive CD8 T cells, and for efficient conjugation and synapse formation tween the T cell and APC leads to formation of an immu- + nological synapse. The IS is a polarized structure that brings between effector CD8 T cells and tumor cells. together the receptors, adhesion molecules, and adaptor proteins necessary for optimal signaling and downstream ef- Materials and Methods fector T cell functions such as cytokine secretion and cyto- Mice and Abs 2 2 toxic activity (3). The activation and cytotoxic activity of The C57BL/6 DNAM-1 / mice were kindly supplied by Marco Colonna CD8+ T cells is fine-tuned by a range of cosignaling mole- (Washington State University School of Medicine, St. Louis, MO) and back- crossed onto the T cell transgenic OT-1 mouse background (Peter MacCallum cules, such as members of the CD28 family (4). Another less 2 2 Cancer Centre). OT-1 DNAM-1+/+ and OT-I DNAM-1 / littermates were characterized group of costimulatory molecules important for used for all experiments. The Abs for flow cytometry were rat anti-Va2, -CD62L, + CD8 T cell function are those of the Ig superfamily of -CD25, -CD69, -CD44, -CD127, -CD107a, mouse anti–granzyme B, –IFN-g *Cancer Immunology, Peter MacCallum Cancer Centre, East Melbourne 3002, Victo- Address correspondence and reprint requests to Dr. Jane Oliaro, Peter MacCallum Cancer ria, Australia; †Centre for Micro-Photonics, Swinburne University, Hawthorn 3122, Centre, East Melbourne 3002, VIC, Australia. E-mail address: [email protected] Victoria, Australia; ‡Department of Immunology, Monash University, Clayton 3168, x The online version of this article contains supplemental material. Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of { Melbourne, Parkville 3052, Victoria, Australia; and Immunology in Cancer and Infec- Abbreviations used in this article: D, distal; DC, dendritic cell; DNAM-1, DNAX tion Laboratory, Queensland Institute of Medical Research, Herston 4006, Queensland, accessory molecule 1; MTOC, microtubule-organizing center; P, proximal. Australia Ó Received for publication August 22, 2013. Accepted for publication November 15, Copyright 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 2013. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1302197 554 CUTTING EDGE: DNAM-1–DEFICIENT T CELLS SHOW IMMUNE SYNAPSE DEFECTS and –TNF-a (BD Biosciences), and anti-DNAM-1 (Biolegend); for microscopy, using a Fluoview FV1000 confocal microscope (Olympus, NY) mounted with they were purified rat anti–LFA-1 and -CD43 (BD Biosciences), phalloidin- a603 oil immersion objective (NA 1.42). T cells selected for protein scoring rhodamine (Molecular Probes), rabbit anti-GM1 (Calbiochem, MERK Milli- had a single contact site with one tumor cell and polarized microtubule- pore, Darmstadt, Germany), and rabbit and rat anti-tubulin (Rockland). organizing center (MTOC). Polarization to the synapse was determined by Secondary Abs conjugated to Alexa Fluorophores and ProLong antifade with quantitating the amount of nonnuclear fluorescence in the proximal (P) re- DAPI were purchased from Molecular Probes. gion (first third of T cell closest to tumor cell) and distal (D) region (rest of T cell), and the ratio was determined by P-D/P+D where values approaching In vitro T cell assays 1 represent strong polarization to the interface of the two cells (Supplemental Fig. 2C). Data were acquired using Matlab and TACTICS software (19). Naive T cells were purified from splenocytes isolated from OT-1 DNAM-1+/+ or 2 2 DNAM-1 / mice by negative selection using an EasySep magnetic separation Statistical analyses system (Stemcell Technologies, Vancouver, BC, Canada). Immature dendritic cells (DCs) were generated as previously described (17). For proliferation assays, Statistical significance was determined using an unpaired Student t test. isolated naive T cells were labeledwithCFSEandincubatedwith1mM SIINKEL-pulsed DCs. The cells were harvested and analyzed for proliferation Results and Discussion peaks by flow cytometry or for the concentration of cytokines in the supernatant DNAM-1 is required for optimal expansion of naive CD8+ T cells in using a Mouse Inflammation Cytometric Bead Array kit (BD Biosciences) after 72 h. Intracellular staining was performed using Cytofix/Cytoperm reagents response to Ag presentation (BD Biosciences). Cytotoxic activity of activated T cells was measured by a Because DNAM-1 has been implicated in impaired T cell re- standard chromium release assay (18) using chromium-labeled MC38-OVA tumor cells or labeled/SIINFEKL-pulsed DCs as targets. For the conjugation sponses to infection in vivo (11), we first determined whether assay, activated T cells (day 5) were labeled with CellTrace Violet Dye (Mo- naive T cells deficient for DNAM-1 responded normally to lecular Probes) and incubated with CFSE-labeled, SIINFEKL-pulsed EL4 tu- Ag presentation. We used naive CD8+ T cells from OT-I mor cells at 37˚C. The cells were vortexed to separate any non-Ag-specific DNAM-1 wild-type (DNAM-1+/+) or deficient (DNAM- Downloaded from conjugates, and the cells were fixed in 4% paraformaldehyde and analyzed by 2/2 flow cytometry for the presence of double-positive conjugates.
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