HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0803441v1 183/3/1587    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Diekmann, J. Articles by Topp, M. S. PubMed PubMed Citation Articles by Diekmann, J. Articles by Topp, M. S.

Processing of Two Latent Membrane Protein 1 MHC Class I Epitopes Requires Tripeptidyl Peptidase II Involvement¹

Jan Diekmann^*, Eleni Adamopoulou^*, Olaf Beck, Georg Rauser, Sarah Lurati^*, Stefan Tenzer, Hermann Einsele^*, Hans-Georg Rammensee^¶, Hansjörg Schild and Max S. Topp^2,*

^* Medical Clinic und Policlinic II, Julius-Maximilian University of Wuerzburg, Wuerzburg, Germany; Pediatric Hematology and Oncology, Johann-Wolfgang Goethe University, Frankfurt, Germany; Miltenyi Biotec, Bergisch Gladbach, Germany; Institute for Immunology, Johannes Gutenberg University Mainz, Mainz, Germany; and ^¶ Department of Immunology, Institute for Cell Biology, Eberhard-Karls University of Tuebingen, Tuebingen, Germany

The EBV Ag latent membrane protein 1 (LMP1) has been described as a potential target for T cell immunotherapy in EBV-related malignancies. However, only a few CD8⁺ T cell epitopes are known, and the benefit of LMP1-specific T cell immunotherapy has not yet been proven. In this work, we studied the processing of the two LMP1 HLA-A02-restricted epitopes, YLLEMLRWL and YLQQNWWTL. We found that target cells endogenously expressing the native LMP1 are not recognized by CTLs specific for these epitopes because the N-terminal part of LMP1 limits the efficiency of epitope generation. We further observed that the proteasome is not required for the generation of both epitopes and that the YLLEMLRWL epitope seems to be destroyed by the proteasome, because blocking of proteasomal activities enhanced specific CTL activation. Activation of LMP1-specific CTLs could be significantly reduced after inhibition of the tripeptidyl peptidase II, suggesting a role for this peptidase in the processing of both epitopes. Taken together, our results demonstrate that the MHC class I-restricted LMP1 epitopes studied in this work are two of very few epitopes known to date to be processed proteasome independently by tripeptidyl peptidase II.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ J.D. was supported by the Jürgen Manchot Stiftung. E.A., H.E., and M.S.T. were supported by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 479 C12). S.T. and H.S. were supported by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 490 E6, Z3).

² Address correspondence and reprint requests to Dr. Max S. Topp, Medical Clinic and Policlinic II, Julius-Maximilians University of Wuerzburg, Roentgenring 11, D-97070 Wuerzburg, Germany. E-mail address: Topp_M{at}medizin.uni-wuerzburg.de

³ Abbreviations used in this paper: TPPII, tripeptidyl peptidase II; HD, Hodgkin‘s disease; ICS, intracellular IFN- staining; LCL, EBV-transformed B lymphoid cell line; LMP, latent membrane protein; NGFR, human nerve growth factor receptor; POMP, proteasomal maturation protein; siRNA, small interfering RNA; TM, transmembrane domain; TOP, thimet oligopeptidase.