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T Lymphocytes + to Recognition by CD8 Caspases in Virus-Infected Caspases in Virus-Infected Cells Contribute to Recognition by CD8 + T Lymphocytes Daniel López, Margarita García-Calvo, Geoffrey L. Smith and Margarita Del Val This information is current as of September 28, 2021. J Immunol 2010; 184:5193-5199; Prepublished online 26 March 2010; doi: 10.4049/jimmunol.1000050 http://www.jimmunol.org/content/184/9/5193 Downloaded from References This article cites 51 articles, 28 of which you can access for free at: http://www.jimmunol.org/content/184/9/5193.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 28, 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 © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Caspases in Virus-Infected Cells Contribute to Recognition by CD8+ T Lymphocytes Daniel Lo´pez,* Margarita Garcı´a-Calvo,† Geoffrey L. Smith,‡ and Margarita Del Val*,x CD8+ cytotoxic T lymphocytes recognize infected cells in which MHC class I molecules present pathogen-derived peptides that have been processed mainly by proteasomes. Many infections induce a set of proteases, the caspases involved in apoptosis or inflammation. In this study, we report that processing and presentation of a short vaccinia virus-encoded Ag can take place also by a nonproteasomal pathway, which was blocked in infected cells with chemical inhibitors of caspases. By cleaving at noncanonical sites, at least two caspases generated antigenic peptides recognized by T lymphocytes. The sites and the peptidic products were partially overlapping but different to those used and produced by proteasomes in vitro. Antigenic natural peptides produced in infected cells by either pathway were quantitatively and qualitatively similar. Finally, coexpression of the natural vaccinia virus protein B13, which is an inhibitor of caspases and apoptosis, impaired Ag presentation by the caspase pathway in infected cells. Downloaded from These data support the hypothesis that numerous cellular proteolytic systems, including those induced during infection, such as caspases involved in apoptosis or in inflammation, contribute to the repertoire of presented peptides, thereby facilitating im- munosurveillance. The Journal of Immunology, 2010, 184: 5193–5199. he initial event for Ag presentation of pathogen-derived pected that these proteases are dedicated to Ag processing, their + epitopes is the proteolytic processing of newly synthesized peptidic products could be useful for Ag presentation to CD8 http://www.jimmunol.org/ T pathogen proteins. The proteasome is the primary and major T lymphocytes. These proteases could thus expand the number of proteolytic complex involved in the cytosolic generation of peptides tissues and physiological and pathological situations compatible (1). This multicatalytic endoprotease is not dedicated to Ag pro- with Ag presentation, as well as the range of pathogen-derived se- cessing and produces a broad diversity of peptides. Among them, quences available for recognition by CD8+ T lymphocytes. a small fraction of the correct epitope or NH2-terminally extended Infection by pathogens and the subsequent variety of immune precursors can be used for MHC class I Ag presentation. These responses may affect the cellular proteolytic machinery in contrasting epitope precursor peptides may be N-terminally trimmed by ami- ways. Induction of apoptosis after infection by many pathogens is nopeptidases in the cytosol (2). The peptides are then transported by a widespread phenomenon (7, 8), which always induces activation TAP to the endoplasmic reticulum lumen and usually require further of a set of endoproteases, the caspases. Caspases are a family of cy- by guest on September 28, 2021 trimming to attain the final size epitope. This is performed mainly toplasmic cysteine proteases, some of which are essential for pro- by endoplasmic reticulum aminopeptidases (3). Finally, binding to grammed cell death in a variety of species, whereas others are nascent MHC class I molecules generates the antigenic complex involved in inflammatory responses (9). They can be detected in recognized by antiviral CD8+ CTLs at the infected cell surface. many different types of cells undergoing apoptosis, regardless of In addition to proteasome-independent and TAP-independent Ag- their origin or the death stimulus. Initiator caspases are the first to processing secretory pathways (4), tripeptidyl peptidase II is the only be activated, followed by effector caspases, which act on cellular endoproteolytic activity that can generate pathogen-derived peptides target molecules. In recent years, over 14 different caspases have been in the cytosol when proteasomes are inhibited (5, 6). The potential identified in mammals (9). They are synthesized as zymogens with role of other cytosolic endoproteases in the processing of MHC no or very low intrinsic enzymatic activity. Direct aggregation of class I viral ligands remains to be elucidated. Although it is not ex- initiator caspases after the triggering stimulus is sufficient to promote self-processing to generate active heterotetramers. Downstream caspases are then activated proteolytically in a cascade fashion. x *Centro Nacional de Microbiologı´a, Instituto de Salud Carlos III; Centro de Biologı´a In a previous study (10), we investigated Ag processing in cells Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientı´ficas, Universidad Auto´noma de Madrid, Madrid, Spain; †Department of Metabolic Disorders and Diabetes, infected with recombinant vaccinia viruses (rVACVs) encoding Merck Research Laboratories, Rahway, NJ 07065; and ‡Department of Virology, Faculty two closely related miniproteins, encompassing murine CMV of Medicine, Imperial College London, St. Mary’s Campus, London, United Kingdom pp89 immunodominant epitope (11). In that study, we defined the Received for publication January 7, 2010. Accepted for publication February 24, redundant role of proteasomes in endogenous Ag processing of 2010. short Ags. In the current study, we have characterized an addi- This work was supported by grants provided by the European Union, Ministerio de Ciencia e Innovacio´n, Comunidad de Madrid, and Instituto de Salud Carlos III (to tional proteasome-independent pathway for Ag processing of one M.D.V.) and Programa Ramo´n y Cajal, Comunidad de Madrid, and Instituto de Salud of these miniproteins, which operates when apoptosis is induced Carlos III (to D.L.). G.L.S. is a Wellcome Principal Research Fellow. by vaccinia virus infection, and demonstrate that caspases can Address correspondence and reprint requests to Dr. Margarita Del Val, Centro de generate viral antigenic peptides recognized by CTLs. Biologı´a Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientı´ficas, c/Nicola´s Cabrera 1, Universidad Auto´noma de Madrid, E-28049 Madrid, Spain. E-mail address: [email protected] Materials and Methods Abbreviations used in this paper: HBe, hepatitis B virus e Ag; LC, lactacystin; MS, Mice mass spectrometry; RP-HPLC, reversed phase-HPLC; rVACV, recombinant vaccinia d virus; WR, Western Reserve. BALB/c mice (H-2 haplotype) were bred in our colony in accordance with national regulations. Animal studies were approved by the review board of Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 Instituto de Salud Carlos III (Madrid, Spain). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1000050 5194 MHC CLASS I Ag PRESENTATION AND APOPTOSIS Reagents Proteasome and caspase digestion assays Lactacystin (LC) was purchased from Dr. E. J. Corey (Harvard University, Caspases that were selectively expressed in bacteria and 20S proteasomes Boston, MA). Benzyloxycarbonyl-VAD-fluoromethyl ketone (z-VAD-fmk) were purified as described (18, 19). m19 digestions by caspases and pro- and z-FA-fmk inhibitors were from Bachem (Weil am Rhein, Germany). All teasome were performed as follows (18, 19): the m19 peptide, dissolved in three were used at 50 mM both for in vitro digestions and for cell-based DMSO, was incubated overnight at room temperature with micromolar experiments. Ac-WEHD-CHO, Ac-YVAD-CHO, and Ac-DEVD-CHO cas- concentrations of different proteases (the proteasome and 10 human cas- pase inhibitors used in control digestions were purchased from Peptide In- pases) in 0.2 ml. Digestion time was chosen to mimic time of exposure of stitute (Osaka, Japan). 9pp89 (YPHFMPTNL), m19 (MDIGAYPHFM- m19 to proteases in infected cells. The final concentration of m19 was PTNLAGDPY), and G9I (GPGRAFVTI) peptides were synthesized in an 0.5 mM, and the incubation buffer consisted of 0.1 M HEPES (pH 7.5), Applera (Applied Biosystems, Foster City, CA) peptide synthesizer model 10% sucrose, 0.1% CHAPS, and 10 mM DTT. Postincubation, the samples 433A, purified, and confirmed to be homogeneous by HPLC analysis. were frozen
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