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Dendritic Cell Activation of NK Cells Innate Immune Response By Lyn-Dependent Signaling Regulates the Innate Immune Response by Controlling Dendritic Cell Activation of NK Cells This information is current as Danielle L. Krebs, Manreet K. Chehal, Alexander Sio, of September 25, 2021. Nicholas D. Huntington, Mei Lin Da, Pascal Ziltener, Melissa Inglese, Nicole Kountouri, John J. Priatel, Jessica Jones, David M. Tarlinton, Gary P. Anderson, Margaret L. Hibbs and Kenneth W. Harder J Immunol 2012; 188:5094-5105; Prepublished online 9 Downloaded from April 2012; doi: 10.4049/jimmunol.1103395 http://www.jimmunol.org/content/188/10/5094 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2012/04/09/jimmunol.110339 Material 5.DC1 References This article cites 85 articles, 33 of which you can access for free at: http://www.jimmunol.org/content/188/10/5094.full#ref-list-1 Why The JI? Submit online. by guest on September 25, 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 © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Lyn-Dependent Signaling Regulates the Innate Immune Response by Controlling Dendritic Cell Activation of NK Cells Danielle L. Krebs,*,1 Manreet K. Chehal,*,1 Alexander Sio,* Nicholas D. Huntington,† Mei Lin Da,* Pascal Ziltener,‡ Melissa Inglese,‡ Nicole Kountouri,‡ John J. Priatel,x Jessica Jones,{,‖ David M. Tarlinton,† Gary P. Anderson,{,‖ Margaret L. Hibbs,‡,2,3 and Kenneth W. Harder*,2 The innate immune response is a first line of defense against invading pathogens; however, the magnitude of this response must be tightly regulated, as hyper- or suboptimal responses can be detrimental to the host. Systemic inflammation resulting from bacterial Downloaded from infection can lead to sepsis, which remains a serious problem with high mortality rates. Lyn tyrosine kinase plays a key role in adaptive immunity, although its role in innate immunity remains unclear. In this study, we show that Lyn gain-of-function (Lynup/up) mice display enhanced sensitivity to endotoxin and succumb to upregulated proinflammatory cytokine production at a dose well tolerated by control animals. Endotoxin sensitivity in Lynup/up mice depends on dendritic cells (DCs) and NK cells and occurs though a mechanism involving increased maturation and activation of the DC compartment, leading to elevated production of IFN-g by NK cells. We further show that modulation of endotoxin-induced signal transduction in DCs by Lyn involves the http://www.jimmunol.org/ phosphatases Src homology 2 domain-containing phosphatase-1 and SHIP-1. Collectively, we demonstrate that Lyn regulates DC physiology such that alterations in Lyn-dependent signaling have profound effects on the nature and magnitude of inflammatory responses. Our studies highlight how perturbations in signaling pathways controlling DC/NK cell-regulated responses to microbial products can profoundly affect the magnitude of innate immune responses. The Journal of Immunology, 2012, 188: 5094–5105. he innate immune response serves as a first line of defense an innate immune response to PAMPs leads to leukocyte re- against invading pathogens (1). Pathogens are recognized cruitment to infected tissues and clearance of infection. Impor- T based on their expression of highly conserved pathogen- tantly, the innate immune response must be tightly regulated, as an associated molecular patterns (PAMPs). Innate immune cells of inefficient response could lead to an inability to clear infection, by guest on September 25, 2021 the mononuclear phagocyte system such as monocytes (Mos), whereas an enhanced or prolonged response could lead to auto- macrophages (Mf), and dendritic cells (DCs) recognize PAMPs immunity or shock and organ injury as occurs during sepsis (3). through germline-encoded pattern recognition receptors including Phagocyte recognition of microbial products is not only im- the TLR family (1, 2). LPS is a highly potent PAMP produced portant for initiating inflammatory responses but also for sculpting by Gram-negative bacteria such as Escherichia coli. LPS binds subsequent innate and adaptive responses. Crosstalk between DCs to TLR4 and activates a complex network of signal transduc- and NK cells is critical in both innate and T cell responses (4, 5). A tion cascades leading to cell activation and secretion of proin- large body of literature shows that NK cells require activation by flammatory mediators, including IL-1, IL-6, IL-12, type I IFNs, DCs to reach their full functional potential. In vitro, TLR- TNF-a, IFN-g, chemokines, and NO (3). Appropriate execution of activated DCs secrete IFN-a, IL-12, IL-15 (trans-presented on *Department of Microbiology and Immunology, I3 Research Group, Life Sciences D.M.T. hold fellowships from the National Health and Medical Research Council of Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Australia. M.K.C. held studentships from the Michael Smith Foundation and the Canada; †Division of Immunology, The Walter and Eliza Hall Institute for Medical Canadian Institutes of Health Research. Research, Parkville, Victoria 3052, Australia; ‡Signal Transduction Laboratory, Lud- Address correspondence and reprint requests to Dr. Kenneth W. Harder, Life Sciences wig Institute for Cancer Research, Royal Melbourne Hospital, Parkville, Victoria x Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada. E-mail ad- 3050, Australia; Child and Family Research Institute, Vancouver, British Columbia { dress: [email protected] V5Z 4H4, Canada; Department of Medicine, University of Melbourne, Parkville, Victoria 3010, Australia; and ‖Department of Pharmacology, University of Mel- The online version of this article contains supplemental material. bourne, Parkville, Victoria 3010, Australia Abbreviations used in this article: BALF, bronchoalveolar lavage fluid; BM, bone 1D.L.K. and M.K.C. contributed equally to this work. marrow; BMDC, bone marrow-derived dendritic cell; BMMf, bone marrow-derived macrophage; DC, dendritic cell; DTx, diphtheria toxin; eGFP, enhanced GFP; 2M.L.H. and K.W.H. are cosenior authors. FLT3L-BMDC, dendritic cell derived from bone marrow in FLT3L; GM-BMDC, 3Current address: Department of Immunology, Monash University, Melbourne, Vic- dendritic cell derived from bone marrow in GM-CSF; iNOS, inducible NO synthase; toria, Australia. Mf, macrophage; MFI, mean fluorescence intensity; MHC-I, MHC class I; MHC-II, MHC class II; Mo, monocyte; ODN, oligodeoxynucleotide; PAMP, pathogen- Received for publication November 29, 2011. Accepted for publication March 14, associated molecular pattern; pDC, plasmacytoid dendritic cell; qPCR, real-time 2012. quantitative PCR; RT, reverse transcription; SFK, Src family tyrosine kinase; SHP, This work was supported by grants from the Canadian Institutes of Health Research Src homology 2 domain-containing phosphatase; shRNA, short hairpin RNA; WT, (CIHMOP-86694 to K.W.H.), the Canadian Breast Cancer Foundation (to K.W.H. wild-type. and D.L.K.), the National Health and Medical Research Council of Australia (to K.W.H. and M.L.H.), and the Cooperative Research Centre for Cellular Growth Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 Factors (to M.L.H.). K.W.H. holds a Tier II Canada Research Chair and was sup- ported by a fellowship from the National Cancer Institute of Canada. M.L.H. and www.jimmunol.org/cgi/doi/10.4049/jimmunol.1103395 The Journal of Immunology 5095 IL-15 receptor a-chain), and IL-18, which induce NK cell IFN-g Staphylococcus aureus) were from InvivoGen. ELISA kits for TNF-a, production and cytotoxicity (6–9). Recently, a mouse model of IL-1a, IL-6, IFN-g, IL-12, and IL-10 were from eBioscience or BD inducible DC ablation was used to show that production of type I Biosciences; the ELISA kit for IL-1b was from R&D Systems; and the high ELISA kit for IFN-a was from PBL InterferonSource. Anti-NK1.1 Ab IFNs and IL-15 by CD11c DCs is required for NK cell priming (PK136) was from the Biomedical Research Centre (Vancouver, BC). in response to pathogens or their products (10). Lympholyte-M was from Cedarlane Laboratories. Ab-coupled magnetic Lyn is a member of the Src family of membrane-associated, beads were from Miltenyi Biotec. IL-15 was from Invitrogen. GM-CSF, nonreceptor protein tyrosine kinases (SFKs) and is expressed in FLT3L, and L cell-conditioned medium (a source of M-CSF) were pro- duced and standardized in our laboratories. all leukocytes except T cells (11). Lyn is activated in response to a wide range of receptors and/or stimuli, including the BCR, CD40, Mice LPS, cytokines, and integrins. Interestingly, Lyn can act as either 2 2 Rag12/2 (33), Lyn / (16), Lynup/up (21), CD11c-DTR/GFP (34), SHIP- a positive or a negative regulator of signal transduction, depend- 12/2 (35), and MeV/MeV (36) mice have been previously described. Mice ing on the type of stimulus, developmental stage of the cell and were C57BL/6 generation .10 genetic background except SHIP-12/2, extracellular environment. Negative regulation occurs when Lyn which were mixed 129Ola 3 C57BL/6. Animal experimentation was phosphorylates tyrosine residues within ITIMs present in inhibitory performed in accordance with the University of British Columbia Animal proteins such as CD22, FcgRIIB1, PIR-B, and SIRPa that are Care Committee, the Canadian Council of Animal Care, and/or the Ludwig Institute for Cancer Research and the Department of Surgery Animal localized at the plasma membrane.
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