Original Article

Differential Influence on Cytotoxic T Lymphocyte Epitope Presentation by Controlled Expression of Either Proteasome Immunosubunits or PA28

Correspondence to: Ferry Ossendorp, Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Tel:31-71-526-3843 Fax:31-71-521-6751 E-mail:ossendorp{at}mail.medfac.leidenuniv.nl.

The proteasome is the principal provider of major histocompatibility complex (MHC) class I–presented peptides. Interferon (IFN)- induces expression of three catalytically active proteasome subunits (LMP2, LMP7, and MECL-1) and the proteasome-associated activator PA28. These molecules are thought to optimize the generation of MHC class I–presented peptides. However, known information on their contribution in vivo is very limited. Here, we examined the antigen processing of two murine leukemia virus-encoded cytotoxic T lymphocyte (CTL) epitopes in murine cell lines equipped with a tetracycline-controlled, IFN-–independent expression system. We thus were able to segregate the role of the immunosubunits from the role of PA28. The presence of either immunosubunits or PA28 did not alter the presentation of a subdominant murine leukemia virus (MuLV)-derived CTL epitope. However, the presentation of the immunodominant MuLV-derived epitope was markedly enhanced upon induction of each of these two sets of genes. Thus, the IFN-–inducible proteasome subunits and PA28 can independently enhance antigen presentation of some CTL epitopes. Our data show that tetracycline-regulated expression of PA28 increases CTL epitope generation without affecting the 20S proteasome composition or half-life. The differential effect of these IFN-–inducible proteins on MHC class I processing may have a decisive influence on the quality of the CTL immune response.

Key Words: antigen processing, major histocompatibility complex class I, immunoproteasomes, PA28, murine leukemia virus

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Yamano, T., Sugahara, H., Mizukami, S., Murata, S., Chiba, T., Tanaka, K., Yui, K., Udono, H. (2008). Allele-Selective Effect of PA28 in MHC Class I Antigen Processing. J. Immunol. 181: 1655-1664 [Abstract] [Full Text]  
• Textoris-Taube, K., Henklein, P., Pollmann, S., Bergann, T., Weisshoff, H., Seifert, U., Drung, I., Mugge, C., Sijts, A., Kloetzel, P.-M., Kuckelkorn, U. (2007). The N-terminal Flanking Region of the TRP2360-368 Melanoma Antigen Determines Proteasome Activator PA28 Requirement for Epitope Liberation. J. Biol. Chem. 282: 12749-12754 [Abstract] [Full Text]  
• Weinzierl, A. O., Lemmel, C., Schoor, O., Muller, M., Kruger, T., Wernet, D., Hennenlotter, J., Stenzl, A., Klingel, K., Rammensee, H.-G., Stevanovic, S. (2007). Distorted Relation between mRNA Copy Number and Corresponding Major Histocompatibility Complex Ligand Density on the Cell Surface. Mol. Cell. Proteomics 6: 102-113 [Abstract] [Full Text]  
• Gregerson, D. S., Lew, K. L., McPherson, S. W., Heuss, N. D., Ferrington, D. A. (2006). RPE Cells Resist Bystander Killing by CTLs, but Are Highly Susceptible to Antigen-Dependent CTL Killing. IOVS 47: 5385-5394 [Abstract] [Full Text]  
• Pang, K. C., Sanders, M. T., Monaco, J. J., Doherty, P. C., Turner, S. J., Chen, W. (2006). Immunoproteasome Subunit Deficiencies Impact Differentially on Two Immunodominant Influenza Virus-Specific CD8+ T Cell Responses. J. Immunol. 177: 7680-7688 [Abstract] [Full Text]  
• Strehl, B., Joeris, T., Rieger, M., Visekruna, A., Textoris-Taube, K., Kaufmann, S. H. E., Kloetzel, P.-M., Kuckelkorn, U., Steinhoff, U. (2006). Immunoproteasomes Are Essential for Clearance of Listeria monocytogenes in Nonlymphoid Tissues but Not for Induction of Bacteria-Specific CD8+ T Cells. J. Immunol. 177: 6238-6244 [Abstract] [Full Text]  
• Szalay, G., Meiners, S., Voigt, A., Lauber, J., Spieth, C., Speer, N., Sauter, M., Kuckelkorn, U., Zell, A., Klingel, K., Stangl, K., Kandolf, R. (2006). Ongoing Coxsackievirus Myocarditis Is Associated with Increased Formation and Activity of Myocardial Immunoproteasomes. Am. J. Pathol. 168: 1542-1552 [Abstract] [Full Text]  
• Osterloh, P., Linkemann, K., Tenzer, S., Rammensee, H.-G., Radsak, M. P., Busch, D. H., Schild, H. (2006). Proteasomes shape the repertoire of T cells participating in antigen-specific immune responses. Proc. Natl. Acad. Sci. USA 103: 5042-5047 [Abstract] [Full Text]  
• Wherry, E. J., Golovina, T. N., Morrison, S. E., Sinnathamby, G., McElhaugh, M. J., Shockey, D. C., Eisenlohr, L. C. (2006). Re-evaluating the Generation of a "Proteasome-Independent" MHC Class I-Restricted CD8 T Cell Epitope. J. Immunol. 176: 2249-2261 [Abstract] [Full Text]  
• Chapiro, J., Claverol, S., Piette, F., Ma, W., Stroobant, V., Guillaume, B., Gairin, J.-E., Morel, S., Burlet-Schiltz, O., Monsarrat, B., Boon, T., Van den Eynde, B. J. (2006). Destructive Cleavage of Antigenic Peptides Either by the Immunoproteasome or by the Standard Proteasome Results in Differential Antigen Presentation. J. Immunol. 176: 1053-1061 [Abstract] [Full Text]  
• Ossendorp, F., Fu, N., Camps, M., Granucci, F., Gobin, S. J. P., van den Elsen, P. J., Schuurhuis, D., Adema, G. J., Lipford, G. B., Chiba, T., Sijts, A., Kloetzel, P.-M., Ricciardi-Castagnoli, P., Melief, C. J. M. (2005). Differential Expression Regulation of the {alpha} and {beta} Subunits of the PA28 Proteasome Activator in Mature Dendritic Cells. J. Immunol. 174: 7815-7822 [Abstract] [Full Text]  
• Luciani, F., Kesmir, C., Mishto, M., Or-Guil, M., de Boer, R. J. (2005). A Mathematical Model of Protein Degradation by the Proteasome. Biophys. J 88: 2422-2432 [Abstract] [Full Text]  
• Basler, M., Youhnovski, N., van den Broek, M., Przybylski, M., Groettrup, M. (2004). Immunoproteasomes Down-Regulate Presentation of a Subdominant T Cell Epitope from Lymphocytic Choriomeningitis Virus. J. Immunol. 173: 3925-3934 [Abstract] [Full Text]  
• Monji, M., Nakatsura, T., Senju, S., Yoshitake, Y., Sawatsubashi, M., Shinohara, M., Kageshita, T., Ono, T., Inokuchi, A., Nishimura, Y. (2004). Identification of a Novel Human Cancer/Testis Antigen, KM-HN-1, Recognized by Cellular and Humoral Immune Responses. Clin. Cancer Res. 10: 6047-6057 [Abstract] [Full Text]  
• Khan, S., Zimmermann, A., Basler, M., Groettrup, M., Hengel, H. (2004). A Cytomegalovirus Inhibitor of Gamma Interferon Signaling Controls Immunoproteasome Induction. J. Virol. 78: 1831-1842 [Abstract] [Full Text]  
• Tenzer, S., Stoltze, L., Schonfisch, B., Dengjel, J., Muller, M., Stevanovic, S., Rammensee, H.-G., Schild, H. (2004). Quantitative Analysis of Prion-Protein Degradation by Constitutive and Immuno-20S Proteasomes Indicates Differences Correlated with Disease Susceptibility. J. Immunol. 172: 1083-1091 [Abstract] [Full Text]  
• Vertuani, S., De Geer, A., Levitsky, V., Kogner, P., Kiessling, R., Levitskaya, J. (2003). Retinoids Act as Multistep Modulators of the Major Histocompatibility Class I Presentation Pathway and Sensitize Neuroblastomas to Cytotoxic Lymphocytes. Cancer Res. 63: 8006-8013 [Abstract] [Full Text]  
• Vertegaal, A. C. O., Kuiperij, H. B., Houweling, A., Verlaan, M., van der Eb, A. J., Zantema, A. (2003). Differential Expression of Tapasin and Immunoproteasome Subunits in Adenovirus Type 5- Versus Type 12-transformed Cells. J. Biol. Chem. 278: 139-146 [Abstract] [Full Text]  
• Zaiss, D. M. W., Standera, S., Kloetzel, P.-M., Sijts, A. J. A. M. (2002). PI31 is a modulator of proteasome formation and antigen processing. Proc. Natl. Acad. Sci. USA 99: 14344-14349 [Abstract] [Full Text]  
• Sun, Y., Sijts, A. J. A. M., Song, M., Janek, K., Nussbaum, A. K., Kral, S., Schirle, M., Stevanovic, S., Paschen, A., Schild, H., Kloetzel, P.-M., Schadendorf, D. (2002). Expression of the Proteasome Activator PA28 Rescues the Presentation of a Cytotoxic T Lymphocyte Epitope on Melanoma Cells. Cancer Res. 62: 2875-2882 [Abstract] [Full Text]  
• Kesmir, C., Nussbaum, A. K., Schild, H., Detours, V., Brunak, S. (2002). Prediction of proteasome cleavage motifs by neural networks. Protein Eng Des Sel 15: 287-296 [Abstract] [Full Text]  
• Schultz, E. S., Chapiro, J., Lurquin, C., Claverol, S., Burlet-Schiltz, O., Warnier, G., Russo, V., Morel, S., Levy, F., Boon, T., Van den Eynde, B. J., van der Bruggen, P. (2002). The Production of a New MAGE-3 Peptide Presented to Cytolytic T Lymphocytes by HLA-B40 Requires the Immunoproteasome. JEM 195: 391-399 [Abstract] [Full Text]  
• Khan, S., van den Broek, M., Schwarz, K., de Giuli, R., Diener, P.-A., Groettrup, M. (2001). Immunoproteasomes Largely Replace Constitutive Proteasomes During an Antiviral and Antibacterial Immune Response in the Liver. J. Immunol. 167: 6859-6868 [Abstract] [Full Text]  
• Li, J., Schuler-Thurner, B., Schuler, G., Huber, C., Seliger, B. (2001). Bipartite regulation of different components of the MHC class I antigen-processing machinery during dendritic cell maturation. Int Immunol 13: 1515-1523 [Abstract] [Full Text]  
• Hallermalm, K., Seki, K., Wei, C., Castelli, C., Rivoltini, L., Kiessling, R., Levitskaya, J. (2001). Tumor necrosis factor-{alpha} induces coordinated changes in major histocompatibility class I presentation pathway, resulting in increased stability of class I complexes at the cell surface. Blood 98: 1108-1115 [Abstract] [Full Text]  
• Toes, R.E.M., Nussbaum, A.K., Degermann, S., Schirle, M., Emmerich, N.P.N., Kraft, M., Laplace, C., Zwinderman, A., Dick, T.P., Muller, J., Schonfisch, B., Schmid, C., Fehling, H.-J., Stevanovic, S., Rammensee, H.G., Schild, H. (2001). Discrete Cleavage Motifs of Constitutive and Immunoproteasomes Revealed by Quantitative Analysis of Cleavage Products. JEM 194: 1-12 [Abstract] [Full Text]  
• Chen, W., Norbury, C. C., Cho, Y., Yewdell, J. W., Bennink, J. R. (2001). Immunoproteasomes Shape Immunodominance Hierarchies of Antiviral CD8+ T Cells at the Levels of T Cell Repertoire and Presentation of Viral Antigens. JEM 193: 1319-1326 [Abstract] [Full Text]  
• Kessler, J. H., Beekman, N. J., Bres-Vloemans, S. A., Verdijk, P., van Veelen, P. A., Kloosterman-Joosten, A. M., Vissers, D. C.J., ten Bosch, G. J.A., Kester, M. G.D., Sijts, A., Drijfhout, J. W., Ossendorp, F., Offringa, R., Melief, C. J.M. (2001). Efficient Identification of Novel HLA-A*0201-presented Cytotoxic T Lymphocyte Epitopes in the Widely Expressed Tumor Antigen PRAME by Proteasome-mediated Digestion Analysis. JEM 193: 73-88 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS