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Autoimmune Encephalomyelitis by NK In In Vivo Regulation of Experimental Autoimmune Encephalomyelitis by NK Cells: Alteration of Primary Adaptive Responses This information is current as Robin Winkler-Pickett, Howard A. Young, James M. of September 27, 2021. Cherry, John Diehl, John Wine, Timothy Back, William E. Bere, Anna T. Mason and John R. Ortaldo J Immunol 2008; 180:4495-4506; ; doi: 10.4049/jimmunol.180.7.4495 http://www.jimmunol.org/content/180/7/4495 Downloaded from References This article cites 70 articles, 28 of which you can access for free at: http://www.jimmunol.org/content/180/7/4495.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 • Fast Publication! 4 weeks from acceptance to publication by guest on September 27, 2021 *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 © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology In Vivo Regulation of Experimental Autoimmune Encephalomyelitis by NK Cells: Alteration of Primary Adaptive Responses1,2 Robin Winkler-Pickett,* Howard A. Young,3* James M. Cherry,† John Diehl,† John Wine,* Timothy Back,* William E. Bere,‡ Anna T. Mason,* and John R. Ortaldo* Innate immune responses provide the host with its first line of defense against infections. Signals generated by subsets of lym- phocytes, including NK cells, NKT cells, and APC during this early host response determine the nature of downstream adaptive immune responses. In the present study, we have examined the role of innate NK cells in an autoimmune model through the use of primary immunization with the myelin oligodendrocyte glycoprotein peptide to induce experimental autoimmune enceph- Downloaded from alomyelitis (EAE). Our studies have shown that in vivo depletion of NK cells can affect the adaptive immune responses, because NK cells were found to regulate the degree of clinical paralysis and to alter immune adaptive responses to the myelin oligodendrocyte glycoprotein peptide. The requirement for NK cells was reflected by changes in the T cell responses and diminished clinical disease seen in mice treated with anti-NK1.1, anti-asialo GM1, and selected Ly49 subtype-depleted mice. In addition to alteration in T cell responses, the maturational status of dendritic cells in lymph nodes was altered both quantitatively and qualitatively. Finally, examination of TCR V␤ usage of the brain lymphocytes from EAE mice indicated http://www.jimmunol.org/ a spectra-type change in receptor expression in NK- depleted mice as compared with non-NK-depleted EAE mice. These findings further establish a recently postulated link between NK cells and the generation of autoreactive T cells. The Journal of Immunology, 2008, 180: 4495–4506. ncreasing evidence has emerged regarding the potential NK cells in the regulation of dendritic cell (DC)4 maturation in role for NK cells in regulating adaptive immune responses. both humans (4, 5) and mice (5, 6). I Early studies in the CMV infection models clearly dem- In many autoimmune diseases, lymphocytes have been shown to onstrated the important regulatory role of NK cells in the CD8- be the effector cells responsible for damage to the tissue target. T by guest on September 27, 2021 mediated T cell responses (1, 2). In addition to a role in con- cells and B cells, as part of the acquired arm of immunity, have trolling viral infections, NK cells producing IFN-␥ have long been known as key inducers of a variety of autoimmune dis- recently been shown to also regulate generation of T cell im- eases. T cells and B cells have been implicated in uveitis, hemo- munity (3) in a parasitic infection (Toxoplasma gondii). This lytic anemia, colitis, myasthenia gravis, lupus, and rheumatoid ar- innate-adaptive interface has been shown to involve a role for thritis among other diseases (7–12). NK cells, being part of the innate immune system, have been implicated in such autoimmune diseases as diabetes and insulitis, as well as rheumatoid arthritis (13–15). Experimental autoimmune encephalomyelitis (EAE) is a prototypic autoimmune disease induced in laboratory animals, *Laboratory of Experimental Immunology, Cancer and Inflammation Program, Na- bearing significant similarities to multiple sclerosis in clinical and tional Cancer Institute-Center for Cancer Research, †SAIC, Gene Expression Labo- ‡ histopathological aspects (16, 17). EAE is known to be mediated ratory, and Basic Research Laboratory, SAIC-Frederick, National Cancer Institute- ϩ Frederick, Frederick, MD 21702 by CD4 T cells that recognize peptides derived from encephali- Received for publication October 18, 2007. Accepted for publication January togenic proteins of the CNS. Cytokines, particularly TNF-␣, are 27, 2008. considered to be the mediators of the pathology that is observed in The costs of publication of this article were defrayed in part by the payment of page the CNS with conflicting analyses of their effects reported (18). In charges. This article must therefore be hereby marked advertisement in accordance the mouse, the disease is characterized by a paralysis proceeding with 18 U.S.C. Section 1734 solely to indicate this fact. from the hind limbs to the forelimbs. Paralysis initiates within 2 1 This work was supported in whole or in part with federal funds from the Na- tional Cancer Institute, National Institutes of Health, under Contract N01-CO- wk of injection of a myelin oligodendrocyte glycoprotein (MOG) 12400. This work was also supported in part by the Intramural Research Program peptide (19, 20). of the National Institutes of Health, National Cancer Institute, Center for Cancer NK cells are known to be a first line of defense in viral infec- Research. 2 tions. In addition, previous studies have suggested that both NK or The publisher or recipient acknowledges the right of the U.S. government to ϩ retain a nonexclusive, royalty-free license in and to any copyright covering this NK1.1 T (NKT) cells serve as regulatory cells in some T cell- article. The content of this publication does not necessarily reflect the views or mediated experimental autoimmune diseases, including murine policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. 3 Address correspondence and reprint requests to Dr. Howard A. Young, Labo- ratory of Experimental Immunology, Cancer and Inflammation Program, 4 Abbreviations used in this paper: DC, dendritic cell; EAE, experimental autoim- 1050 Boyles Street, Frederick, MD 21702. E-mail address: younghow@mail. mune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; PT, pertussis nih.gov toxin; LN, lymph node; CT, threshold cycle. www.jimmunol.org 4496 A ROLE FOR NK CELLS IN THE DEVELOPMENT OF EAE models of encephalomyelitis (EAE) (21, 22), colitis (23), and di- the procedures outlined in the “Guide for the Care and Use of Laboratory abetes (24). Studies by Ljunggren and colleagues (25, 26) have Animals (National Institutes of Health Publication no. 86-23, 1985). detailed the contribution of NK cells in primary B cell-mediated Antibodies autoimmunity. Autoantibodies produced by B cells are the primary cause of disease in a variety of autoimmune conditions, including The mAbs 4E5 (Ly49D), 3D10 (Ly49H), and 3A10 (NKG2D) were pro- vided by Dr. W. Yokoyama (Washington University, St. Louis, MO). The hemolytic anemia, thyroiditis, stiff man syndrome, pemphigus vul- mAb 1F8 (Ly49C/I/H) was a gift from Dr. M. Bennett (University of Texas garis, and systemic lupus erythematosis. Shi et al. (27) demon- Southwestern Medical Center, Dallas, TX). Fluorochrome-labeled isotype- strated that MOG failed to induce EAE in IL-18Ϫ/Ϫ mice. EAE specific controls were purchased from BD Biosciences and BD Pharm- could be observed upon IL-18 administration but disease re- ingen along with fluorochrome-labeled Abs to Ly49D, NK1.1, CD4, CD3␧, and CD80. Fluorochrome-labeled Ab to CD86 was purchased quired the presence of IFN-␥-producing NK cells. These find- Ј from eBioscience. Rabbit F(ab )2 anti-rat IgG was used as a cross- ings established an important, unrecognized link between NK linking reagent (MP Biomedicals). Anti-asialo GM1 was purchased cells and autoimmunity in a primary in vivo model system. from Wako Pure Chemical Industries (Japan) and unlabeled anti-NK1.1 More recently, mice lacking CX3CR1 that developed MOG- and 5E6 (Ly49C/I) were prepared by Hazleton Laboratories (Falls ␧ induced EAE demonstrated a reduced recruitment of NK cells Church, VA). Unlabeled anti-CD3 was purchased from BD Bio- sciences and BD Pharmingen. Abs were used for in vivo depletions of to the CNS (28). cell subsets, flow cytometric, or functional studies. Intracellular IFN-␥ In a another report focused on the possible role of NK cells in detection was performed using Ab kits purchased from BD Biosciences the murine EAE model, Zhang et al. (21) noted that in vivo NK and BD Pharmingen. cell depletion resulted in exacerbation of clinical symptoms in Flow cytometry analysis (FCA) wild-type C57BL/6 (B6) mice. In addition, these investigators also Downloaded from found that depletion of NK cells resulted in an increased severity Cells were stained as previously described (29) and analyzed on an LSR flow cytometer (BD Biosciences) or a FACSort flow cytometer retrofitted of symptoms when disease was induced by passive transfer of a with a solid-state 635-nm laser (BD Biosciences).
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