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Epitopes in Vivo -Derived CD8 T Cell Listeria Monocytogenes Dynamic Dynamic Antigen Presentation Patterns of Listeria monocytogenes-Derived CD8 T Cell Epitopes In Vivo This information is current as Mojca Skoberne, Rafaela Holtappels, Herbert Hof and of September 28, 2021. Gernot Geginat J Immunol 2001; 167:2209-2218; ; doi: 10.4049/jimmunol.167.4.2209 http://www.jimmunol.org/content/167/4/2209 Downloaded from References This article cites 41 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/167/4/2209.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 © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Dynamic Antigen Presentation Patterns of Listeria monocytogenes-Derived CD8 T Cell Epitopes In Vivo1 Mojca S˘koberne,* Rafaela Holtappels,† Herbert Hof,* and Gernot Geginat2* Little information exists regarding the presentation of antigenic peptides in infected tissues. In this study the in vivo presentation of four different CD8 T cell epitopes of Listeria monocytogenes was monitored. Peptide presentation was measured by a new, highly sensitive, ex vivo Ag presentation assay that was based on the testing of freshly isolated cells from infected spleens with peptide- specific CD8 T cell lines in an IFN-␥-specific ELISPOT assay. Remarkably, the peptide presentation pattern of splenocytes and that of macrophages purified from spleens of L. monocytogenes-infected mice were different from those of in vitro infected macrophage-like cell lines. The in vivo Ag presentation pattern of splenocytes also exhibited dynamic changes during the first 48 h of infection. In vivo peptide presentation at later time points postinfection was biased toward immunodominant CD8 T cell epitopes, while at an early time point, 6 h postinfection, subdominant and dominant CD8 T cell epitopes were presented with Downloaded from similar strength. In summary, our studies show that Ag presentation during an infection is a highly dynamic process that only can be fully appreciated by the study of cells infected in their physiological environment. The Journal of Immunology, 2001, 167: 2209–2218. he host response against infection with a complex micro- reticulum (6) or the modulation of the immunogenicity of T cell organism comprises T cells specific for a multitude of Ag by variations in the sequences flanking a T cell epitope (7, 8). http://www.jimmunol.org/ T different antigenic peptides. Generally, the magnitude of The murine infection with Listeria monocytogenes is one of the the T cell response against different antigenic peptides exhibits a infection models where the mechanisms governing CD8 T cell remarkably constant hierarchy, and the majority of the responding induction and expansion were studied in detail. Mice infected with T cells are directed against few immunodominant T cell epitopes L. monocytogenes mount MHC class I Kd-restricted CD8 T cell (1). Numerous studies in different infectious disease model sys- responses against peptides encompassing aa 91–99 of listeriolysin tems revealed that the strength of the CD8 T cell response against O (LLO)3 (4); aa 217–225 (9), 449–457 (10), and 476–484 (11) a peptide is the result of the complex interplay of three major of the p60 protein; and aa 84–92 of the listerial metalloprotease factors: the quantity and stability of peptide MHC class I/com- (12), respectively. In vivo the majority of CD8 T cells are specific by guest on September 28, 2021 plexes expressed on APC, the TCR repertoire of the responding T for the immunodominant epitopes LLO91–99 and p60217–225, while cell population, and the suppression of T cells specific for sub- relatively few T cells are directed against the subdominant dominant epitopes by T cells specific for immunodominant epitopes p60449–457 and Mpl84–92 (13). The frequency of epitopes (reviewed in Ref. 2). Ag presentation is certainly required p60476–484-specific CD8 T cells is intermediate between the fre- for the induction and expansion of CD8 T cells. However, only a quency of p60217–225 and that of p60449–457-specific T cells (11). few studies exist about the processing and presentation of anti- Remarkably, among these four L. monocytogenes-derived peptides genic peptides in vivo. In principle, the extraction and quantifica- the immunodominant LLO91–99 is the least abundant endog- tion of naturally processed antigenic peptides allow the direct anal- enously processed peptide in infected cell lines, while the sub- ysis of Ag processing in tissues (3). Due to the relatively large dominant p60449–457 is the most abundant antigenic peptide in number of infected cells required for this method the extraction of infected cell lines (14). Thus, a paradoxical inverse correlation antigenic peptides from organs was only successful in a few model exists between the abundance of naturally processed antigenic pep- infections (4, 5). More indirectly, bacteria and viruses that express tides in infected cells and the frequency of peptide-specific CD8 T genetically engineered proteins were used to analyze the effects of cells in vivo. variations in Ag presentation on the strength of the CD8 T cell It must be kept in mind that the quantitative analysis of peptide response in vivo. Examples are the enhanced immunogenicity of processing is based on in vitro infected cells and that it is not preprocessed Ags that are directly targeted into the endoplasmic known to what extent this in vitro model represents the in vivo situation. Therefore, in the current study the presentation of L. *Institut fu¨r Medizinische Mikrobiologie und Hygiene, Fakulta¨t fu¨r Klinische Medi- monocytogenes-derived antigenic peptides was monitored in vivo. zin Mannheim der Universita¨t Heidelberg, Mannheim, Germany; and †Institut fu¨r We used a novel approach for the direct measurement of Ag Virologie, Universita¨t Mainz, Mainz, Germany presentation in tissues that is based on the testing of in vivo-in- Received for publication February 15, 2001. Accepted for publication June 5, 2001. fected cells with peptide-specific CD8 T cell lines in a sensitive The costs of publication of this article were defrayed in part by the payment of page ELISPOT assay. Remarkably, the peptide presentation pattern of charges. This article must therefore be hereby marked advertisement in accordance splenocytes infected with L. monocytogenes in vivo exhibited dy- with 18 U.S.C. Section 1734 solely to indicate this fact. namic changes during the first 48 h of infection. In light of this new 1 This work was supported by Deutsche Forschungsgemeinschaft Grant GE 1081/1-1. M.S. was supported by the Slovenian Ministry of Science and the Medical Faculty of finding the possible correlation between peptide presentation and the University of Ljubljana. in vivo CD8 T cell expansion and function was reevaluated. 2 Address correspondence and reprint requests to Dr. Gernot Geginat, Institut fu¨r Medizinische Mikrobiologie und Hygiene, Fakulta¨t fu¨r Klinische Medizin Mannheim der Universita¨t Heidelberg, Theodor Kutzer Ufer 1-3, 68167 Mannheim, Germany. 3 Abbreviations used in this paper: LLO, listeriolysin O; AcN, acetonitrile; TFA, E-mail address: [email protected] trifluoroacetic acid; p.i., postinfection. Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00 2210 PRESENTATION OF CD8 T CELL EPITOPES IN VIVO Materials and Methods was 0–5 min of 0% B, 5–55 min linear increase to 50% B, 55–63 min Mice and infection of mice linear increase to 100% B, 63–66 min of 100% B, and 66–74 min linear decrease to 0% B. One-minute fractions were collected and stored at Female BALB/cOlaHsd (H-2d) mice were purchased (Harlan-Winkel- Ϫ70°C. mann, Borchen, Germany), kept under conventional conditions and used at Isolation of naturally processed peptides from infected cell lines was 8–10 wk of age. Mice were infected with L. monocytogenes serovar 1/2a performed similarly. Six hours postinfection (p.i.) ϳ1 ϫ 108 adherent L. EGD in 0.2 ml PBS either i.v. or i.p. as indicated. Infectious doses were monocytogenes-infected P388 or J774 cells were washed twice with ice- 1 ϫ 106 and 1 ϫ 103 CFU i.v. for ex vivo peptide presentation experiments cold PBS and harvested with a cell scraper. Cell pellets were disrupted, and T cell induction studies, respectively. Bacteria used for infection were sonicated, and lysed for 30 min in 2 ml 0.5% TFA supplemented with in the logarithmic growth phase. The bacterial concentration was estimated proteinase inhibitors as described above. Subsequently, cell lysates were from the OD at 600 nm. centrifuged 30 min at 20,000 ϫ g, and supernatants were further purified by ultrafiltration using MICROSEP (Pall-Gelman, Dreieich, Germany) ul- APC, in vitro infection of APC, and CD8 T cell lines trafiltration units with a 10-kDa cutoff. The low Mr fraction was further P815 mastocytoma cells were used as targets in the cell-mediated cytotox- fractionated by HPLC as described above. icity assay. For in vitro infection experiments macrophage-like J774A1 ϫ 8 (J774) and P388D1 (P388) cells were used as APC. Approximately 1 10 P388 or J774 cells were infected with L.
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