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CTLA-4 During Innate Immunity Inflammatory Heart Disease By Cutting Edge: T Cell Ig Mucin-3 Reduces Inflammatory Heart Disease by Increasing CTLA-4 during Innate Immunity This information is current as Sylvia Frisancho-Kiss, Jennifer F. Nyland, Sarah E. Davis, of September 26, 2021. Masheka A. Barrett, Shannon J. L. Gatewood, Dolores B. Njoku, Daniela Cihakova, Ellen K. Silbergeld, Noel R. Rose and DeLisa Fairweather J Immunol 2006; 176:6411-6415; ; doi: 10.4049/jimmunol.176.11.6411 Downloaded from http://www.jimmunol.org/content/176/11/6411 References This article cites 23 articles, 5 of which you can access for free at: http://www.jimmunol.org/content/176/11/6411.full#ref-list-1 http://www.jimmunol.org/ 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 September 26, 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 © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. THE JOURNAL OF IMMUNOLOGY CUTTING EDGE Cutting Edge: T Cell Ig Mucin-3 Reduces Inflammatory Heart Disease by Increasing CTLA-4 during Innate Immunity1 Sylvia Frisancho-Kiss,* Jennifer F. Nyland,*† Sarah E. Davis,*† Masheka A. Barrett,* Shannon J. L. Gatewood,*† Dolores B. Njoku,*‡ Daniela Cihakova,* Ellen K. Silbergeld,† Noel R. Rose,*§ and DeLisa Fairweather2*† Autoimmune diseases can be reduced or even prevented if velopment of acute myocarditis from days 7 to 14 postinfection proinflammatory immune responses are appropriately (p.i.) that progresses to chronic myocarditis and dilated cardio- down-regulated. Receptors (such as CTLA-4), cytokines myopathy (4). Downloaded from (such as TGF-␤), and specialized cells (such as The family of genes encoding T cell Ig mucin (Tim) proteins ؉ ؉ CD4 CD25 T regulatory cells) work together to keep reside in syntenic chromosomal regions (5q33.2 in human; immune responses in check. T cell Ig mucin (Tim) family 11B1.1 in mouse) that are linked to susceptibility to allergy and proteins are key regulators of inflammation, providing an autoimmune diseases (5). Tim-3 is highly expressed on differ- inhibitory signal that dampens proinflammatory re- entiated Th1 cells, with lower levels on monocytes, NK, and sponses and thereby reducing autoimmune and allergic re- NKT cells (6–8). Treatment of mice with Abs that block http://www.jimmunol.org/ sponses. We show in this study that reducing Tim-3 sig- Tim-3 (anti-Tim-3) in a mouse model of multiple sclerosis leads to hyperacute disease with increased numbers of neutro- naling during the innate immune response to viral phils and macrophages and greater demyelination (5, 7, 9, 10), infection in BALB/c mice reduces CD80 costimulatory showing that Tim-3 is important in decreasing inflammation molecule expression on mast cells and macrophages and ؉ (5). Although it is believed that Tim-3 induces tolerance by reduces innate CTLA-4 levels in CD4 T cells, resulting down-regulating inflammation, the precise mechanisms are less in decreased T regulatory cell populations and increased clear. inflammatory heart disease. These results indicate that by guest on September 26, 2021 regulation of inflammation in the heart begins during in- Materials and Methods nate immunity and that Tim-3 signaling on cells of the Myocarditis and anti-Tim-3 treatment innate immune system critically influences regulation of Male BALB/cJ (BALB/c) mice (6–8 wk old) (The Jackson Laboratory) were the adaptive immune response. The Journal of Immu- inoculated i.p. with 103 PFU of a heart-passaged stock of CVB3 (Nancy strain; nology, 2006, 176: 6411–6415. American Type Culture Collection) or control PBS on day 0 and examined at 30 min or 6 h (innate response) or at day 10 or 12 p.i. for myocarditis (acute response) (11). Mice also received one i.p. injection of 100 ␮g of anti-Fc (clone ntigen presentation during innate immunity influ- 93; eBioScience) to reduce nonspecific binding and either 100 ␮g of anti-Tim- 3-blocking Ab (clone 8B.2C12; eBioScience) or control IgG (catalog no. 16- ences the development of the adaptive immune re- 4301; eBioScience) on day 0. Mice were maintained under pathogen-free con- A sponse. The costimulatory molecules CD80 (B7-1) ditions in the animal facility at Johns Hopkins School of Medicine, and and CD86 (B7-2) on APC bind both CD28 and the regulatory approval was obtained from the Animal Care and Use Committee of the Johns molecule CTLA-4. CTLA-4 down-regulates T cells by mecha- Hopkins University for all procedures. ␤ nisms that include TGF- and transcription factor forkhead FACS analysis box p3 (Foxp3)3 expression, T regulatory cell (Treg) induction, Mast cells (MC) and macrophages were separated from heart cells, splenocytes, and reverse signaling via CD80 and CD86 on APC (1, 2). or peritoneal lavage cells using anti-CD117, anti-FITC, or anti-CD45 (eBio- CTLA-4-deficient mice spontaneously develop a lymphoprolif- Science; clone 30-F11) paramagnetic beads on a magnetic column (Miltenyi erative autoimmune response, with particularly severe pancre- Biotec), as described previously (11). MC and macrophages comprise ϳ6% of atitis and myocarditis (3). Coxsackievirus B3 (CVB3) infection the cells isolated from the heart at 6 h p.i., a number similar to the level in uninfected or PBS inoculated mice. Cells were stained with the following mAbs of susceptible BALB/c mice produces inflammatory heart dis- (eBioScience) diluted in 1% FBS in PBS: CD3 (total T cells, clone 17A2), CD4 ease that is similar to the disease observed in humans, with de- (CD4 T cells, clone GK1.5), CD117 (MC, clone ACK2), F4/80 (macrophages, *Department of Pathology, †Department of Environmental Health Sciences, ‡Department 1 This work was supported by National Institutes of Health Grants HL67290, HL70729, of Anesthesiology and Critical Care Medicine, and §W. Harry Feinstone Department of AI51835, ES03819, and T32 ES07141 (to J.F.N.). Molecular Microbiology and Immunology, Johns Hopkins University, Baltimore, MD 2 Address correspondence and reprint requests to Dr. DeLisa Fairweather, Department of 21205 Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins Uni- Received for publication September 8, 2005. Accepted for publication March 22, 2006. versity, 615 North Wolfe Street, Room E7628, Baltimore, MD 21205. E-mail address: [email protected] The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. 3 Abbreviations used in this paper: Foxp3, forkhead box p3; Treg, T regulatory cell; CVB3, Section 1734 solely to indicate this fact. coxsackievirus B3; p.i., postinfection; Tim, T cell Ig mucin; MC, mast cell. Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 6412 CUTTING EDGE: Tim-3 REDUCES INFLAMMATORY HEART DISEASE FIGURE 1. Anti-Tim-3 increases myocarditis. A, BALB/c mice were inoculated with anti-Tim-3 (aTIM3), isotype control IgG Ab (ISO), or PBS control at day 0 of CVB3 infection. Myocarditis was assessed on day 12 as the percentage of the heart with inflammation compared with the overall size of the heart and shown as the mean Ϯ SEM. B–C, Tissues were fixed with formalin and stained with H&E. Original magnification, ϫ20. B, Histopathology of isotype control IgG-treated .p Ͻ 0.05 ,ء .mice. C, Histopathology of anti-Tim-3-treated mice. Experiments were repeated three times with five to seven mice per group clone BM8), CD11b (macrophages and neutrophils, clone M1/70), B220 (B Fluorescence microscopy cells, clone RA3-6B2), Tim-3 (clone 8B.2C12), CD80 (B7-1, clone 16-10A1), D Immune cells were collected by flushing the peritoneal cavity with 1% BSA in CD86 (B7-2, clone GL1), I-A (MHC class II, clone AMS-32.1; BD Pharm- Downloaded from ingen), CD152 (CTLA-4, clone UC10-4B9), CD25 (clone PC61.5), Foxp3 PBS at 30 min or 6 h after CVB3 i.p. infection and compared with PBS, un- (clone FJK-165), and CD28 (clone 37.51). For intracellular staining, cells were infected controls at 0 h. MC and macrophages from the peritoneum were sep- fixed and permeabilized using a BD Cytofix/Cytoperm or anti-mouse Foxp3 arated using paramagnetic beads and labeled using FITC CD117 or F4/80 staining kit (BD Pharmingen). Cell fluorescence was measured using a FACS- (green fluorescence). Biotinylated anti-Tim-3 mAb were labeled with Alexa- Calibur flow cytometer, and data were analyzed using CellQuest software (BD 555 (red fluorescence) (Molecular Probes), and cells were visualized using a Ni- Biosciences). kon E800 Microscope. Images were recorded with a 5-MHz Black and White http://www.jimmunol.org/ by guest on September 26, 2021 FIGURE 2. Tim-3 expression is increased on APC6haf- ter CVB3 infection. A, Peritoneal MC (FITC-CD117) or macrophages (Mac; FITC-F4/80) (green, left column) were costained with Alexa-555 (red, middle column). Merged im- ages (yellow, right column) show colocalization of CD117 or F4/80 with Tim-3 on the surface of cells 30 min after infec- tion. B, Tim-3 expression (solid red line) is increased on peri- toneal MC 6 h after infection by FACS analysis compared with uninfected (filled line) and isotype controls (fine blue line).
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