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Cells T+ MHC Class I Complexes Prime CD8 Dendritic Cells Cross Dendritic Cells Cross-Dressed with Peptide MHC Class I Complexes Prime CD8 + T Cells This information is current as Brian P. Dolan, Kenneth D. Gibbs, Jr and Suzanne of September 29, 2021. Ostrand-Rosenberg J Immunol 2006; 177:6018-6024; ; doi: 10.4049/jimmunol.177.9.6018 http://www.jimmunol.org/content/177/9/6018 Downloaded from References This article cites 37 articles, 21 of which you can access for free at: http://www.jimmunol.org/content/177/9/6018.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 29, 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 © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Dendritic Cells Cross-Dressed with Peptide MHC Class I Complexes Prime CD8؉ T Cells1 Brian P. Dolan, Kenneth D. Gibbs, Jr., and Suzanne Ostrand-Rosenberg2 The activation of naive CD8؉ T cells has been attributed to two mechanisms: cross-priming and direct priming. Cross-priming ,and direct priming differ in the source of Ag and in the cell that presents the Ag to the responding CD8؉ T cells. In cross-priming exogenous Ag is acquired by professional APCs, such as dendritic cells (DC), which process the Ag into peptides that are sub- sequently presented. In direct priming, the APCs, which may or may not be DC, synthesize and process the Ag and present it themselves to CD8؉ T cells. In this study, we demonstrate that naive CD8؉ T cells are activated by a third mechanism, called cross-dressing. In cross-dressing, DC directly acquire MHC class I-peptide complexes from dead, but not live, donor cells by a cell contact-mediated mechanism, and present the intact complexes to naive CD8؉ T cells. Such DC are cross-dressed because they ؉ are wearing peptide-MHC complexes generated by other cells. CD8 T cells activated by cross-dressing are restricted to the MHC Downloaded from class I genotype of the donor cells and are specific for peptides generated by the donor cells. In vivo studies demonstrate that optimal priming of CD8؉ T cells requires both cross-priming and cross-dressing. Thus, cross-dressing may be an important mechanism by which DC prime naive CD8؉ T cells and may explain how CD8؉ T cells are primed to Ags that are inefficiently cross-presented. The Journal of Immunology, 2006, 177: 6018–6024. ϩ ϩ ntigen presentation to CD8 T lymphocytes is postu- fected DC also directly present viral Ags to CD8 T cells (12, 13). http://www.jimmunol.org/ lated to occur through two mechanisms, which differ Ultimately, CD8ϩ T cell priming to viral infections may be the from each other by the type of cell that processes and result of both cross-priming and direct priming (14). Cross-prim- A ϩ presents the peptide Ag. According to the direct Ag presentation ing has also been demonstrated for CD8 T cells activated to mechanism, CD8ϩ T cells recognize their cognate peptide-MHC tumor Ags (15–17); however, other studies suggest that priming of class I complexes on the surface of the cells that synthesized the tumor-specific CD8ϩ T cells occurs through the direct presentation Ag, such as virally infected cells or malignant cells (1). Alterna- of tumor Ags by tumor cells (18, 19). Therefore, a consensus tively, CD8ϩ T cells recognize peptide-MHC class I complexes on model for CD8ϩ T cell priming does not exist. the surface of cells, which have captured exogenously synthesized In this study, we report that CD8ϩ T cells can be primed by a Ag, and subsequently process and present the Ag bound to their third mechanism, termed cross-dressing. During cross-dressing, by guest on September 29, 2021 own MHC class I proteins. This latter mechanism is termed cross- peptide-MHC class I complexes are transferred to DC from dead presentation, and dendritic cells (DC)3 are the predominant cell donor cells that synthesized the complexes. Recipient DC then use population that captures and presents Ag (2, 3). If the process of the acquired peptide-MHC class I complexes to activate CD8ϩ T cross-presentation results in the activation of naive T cells, then the cells that are peptide specific and restricted to the MHC class I T cells have been activated by cross-priming. genotype of the donor cells. Optimal priming of CD8ϩ T cells Although compelling evidence supports cross-priming as the probably results from a combination of cross-dressing and cross- principal mechanism for activating naive CD8ϩ T cells (2, 4, 5), priming, because cross-dressing efficiently activates DC that are other studies are consistent with CD8ϩ T cells being activated by not efficiently activated by cross-priming. the direct presentation mechanism (6, 7). The concept of cross- priming is supported by many reports demonstrating that CD8ϩ T cells specific for virally infected cells are primed by DC cross- Materials and Methods presenting virally derived peptides (8–11), although virally in- Mice Breeding stocks of BALB/c, C57BL/6, FVB, OT-I, and CD11c-diphtheria toxin receptor (DTR) (Itgax-DTR/enhanced GFP) mice on a BALB/c back- Department of Biological Sciences, University of Maryland Baltimore County, Bal- ground were from The Jackson Laboratory. MHC I/IIϪ/Ϫ mice and OT-I/ timore, MD 21250 RAG 2Ϫ/Ϫ mice were from Taconic Farms. CD11c-DTR mice were Received for publication June 5, 2006. Accepted for publication August 7, 2006. screened, as described (20). OT-I mice were identified by immunofluores- cent staining of PBLs for CD8 and V␣2. H-2b/CD11c-DTRϩ/Ϫ mice were The costs of publication of this article were defrayed in part by the payment of page generated by crossing CD11c-DTR mice with MHC class I/II-deficient charges. This article must therefore be hereby marked advertisement in accordance ϩ/Ϫ with 18 U.S.C. Section 1734 solely to indicate this fact. mice, and the CD11c-DTR F1 offspring were backcrossed to MHC ϩ/Ϫ 1 class I/II-deficient mice. CD11c-DTR F2 mice that were negative for This work was supported by National Institutes of Health Grants CA52527, both MHC class I and II (identified by immunofluorescence staining for the CA84232, and CA115880, Department of Defense Grant DAMD-17-01-1-0312, and ϩ ϩ Susan G. Komen Foundation Grant BCTR0503885. B.P.D. is supported by Depart- absence of peripheral CD4 and CD8 T cells) were then crossed with ment of Defense Grant DAMD-17-03-1-0334 predoctoral fellowship, and K.D.G. is C57BL/6 mice. The F1 mice of this cross were subsequently used in experi- supported by a National Institutes of Health MARC-U-STAR training grant ments. All animal procedures were approved by the University of Maryland (GM08663). Baltimore County Institutional Animal Care and Use Committee. 2 Address correspondence and reprint requests to Dr. Suzanne Ostrand-Rosenberg, Department of Biological Sciences, University of Maryland, 1000 Hilltop Circle, Cells, transfections, and Abs Baltimore, MD 21250. 3 Abbreviations used in this paper: DC, dendritic cell; BMDC, bone marrow-derived B16.BL6 8.2, A20, EL4, and EL4/OVA were cultured, as described (20– DC; DTR, diphtheria toxin receptor; DTx, diphtheria toxin. 22). NIH3T3 cells were grown in DMEM supplemented with 10% FCS Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 The Journal of Immunology 6019 (HyClone) DAP/OVA cells (23) were maintained in RPMI 1640 (Bioflu- Ag presentation assays ids) supplemented with 10% FCS, 1 mM HEPES (Invitrogen Life Tech- 5 nologies), 5 ϫ 10Ϫ6 M 2-ME (Sigma-Aldrich), 400 ␮g/ml G418 (Calbio- Splenic DC were plated in 96-well plates in DC medium at 10 cells/well. ϫ chem), and 200 ␮g/ml zeocin (Invitrogen Life Technologies). Medium for One hour later, freeze-thawed donor cells at 3–4 cell equivalents or all cell lines contained 1% penicillin, 1% streptomycin, 1% gentamicin soluble OVA protein (Sigma-Aldrich) were added. Following a 3-h incu- (Biofluids), and 1% Glutamax (Invitrogen Life Technologies) (complete bation, wells were washed with excess PBS to remove dead material. medium). The DAP/OVA/Kb cell line was generated by transfection using BMDC were incubated with freeze-thawed donor cells or with soluble OVA protein for 3 h, the mixture was passaged over Ficoll to remove dead Lipofectamine Plus (Invitrogen Life Technologies), according to the man- 5 ␮ b material, and the purified BMDC were plated at 10 cells/well in 96-well ufacturer’s recommendations. Approximately 4 g of the K plasmid ϩ ϩ pKbT.8 (24, 25) was linearized with PvuI (Fermentas Life Sciences), eth- plates. CD8 OT-I T cells were isolated using CD8 T cell isolation kits, anol precipitated, resuspended in 100 ␮l of DMEM (Biofluids), mixed with according to the manufacturer’s suggested protocol (Miltenyi Biotec), and 5 ␮ 16 ␮l of Plus reagent, and incubated for 15 min at room temperature. One added to the purified BMDC at 10 cells/well for a total volume of 200 l hundred microliters of DMEM containing 10 ␮l of lipofectamine was then of complete RPMI 1640/well.
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