Original Article

Human Transporters Associated with Antigen Processing (TAPs) Select Epitope Precursor Peptides for Processing in the Endoplasmic Reticulum and Presentation to T Cells

Correspondence to: Peter M. van Endert, INSERM U25, 161 rue de Sèvres, 75743 Paris cedex 15, France. Tel:33-1-44492563 Fax:33-1-43062388 E-mail:vanendert{at}necker.fr.

Antigen presentation by major histocompatibility complex (MHC) class I molecules requires peptide supply by the transporters associated with antigen processing (TAPs), which select substrates in a species- and, in the rat, allele-specific manner. Conflicts between TAPs and MHC preferences for COOH-terminal peptide residues in rodent cells strongly reduce the efficiency of MHC class I antigen presentation. Although human TAP is relatively permissive, some peptide ligands for human histocompatibility leukocyte antigen class I molecules are known to possess very low TAP affinities; the significance of these in vitro findings for cellular antigen presentation is not known. We studied two naturally immunodominant viral epitopes presented by HLA-A2 that display very low affinities for human TAP. Low TAP affinities preclude minimal epitope access to the endoplasmic reticulum (ER) and assembly with HLA-A2 in vitro, as well as presentation by minigene-expressing cells to cytotoxic T lymphocytes. However, NH₂-terminally but not COOH-terminally extended epitope variants with higher TAP affinities assemble in vitro and are presented to cytotoxic T lymphocytes with high efficiency. Thus, human TAP can influence epitope selection and restrict access to the ER to epitope precursors. Analysis of TAP affinities of a panel of viral epitopes suggests that TAP selection of precursors may be a common phenomenon for HLA-A2–presented epitopes. We also analyzed HLA-A2–eluted peptides from minigene-expressing cells and show that an NH₂-terminally extended variant with low A2 binding affinity undergoes ER processing, whereas another with high affinity is presented unmodified. Therefore, the previously reported aminopeptidase activity in the ER can also act on TAP-translocated peptides.

Key Words: antigen presentation, ABC transporters, immunodominant epitopes, HLA class I, aminopeptidases

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

This article has been cited by other articles:

• Wei, C.-H., Sherman, L. A. (2007). N-Terminal Trimer Extension of Nominal CD8 T Cell Epitopes Is Sufficient to Promote Cross-Presentation to Cognate CD8 T Cells In Vivo. J. Immunol. 179: 8280-8286 [Abstract] [Full Text]  
• Samino, Y., Lopez, D., Guil, S., Saveanu, L., van Endert, P. M., Del Val, M. (2006). A Long N-terminal-extended Nested Set of Abundant and Antigenic Major Histocompatibility Complex Class I Natural Ligands from HIV Envelope Protein. J. Biol. Chem. 281: 6358-6365 [Abstract] [Full Text]  
• Bruder, D., Nussbaum, A. K., Gakamsky, D. M., Schirle, M., Stevanovic, S., Singh-Jasuja, H., Darji, A., Chakraborty, T., Schild, H., Pecht, I., Weiss, S. (2006). Multiple synergizing factors contribute to the strength of the CD8+ T cell response against listeriolysin O. Int Immunol 18: 89-100 [Abstract] [Full Text]  
• Culina, S., Lauvau, G., Gubler, B., van Endert, P. M. (2004). Calreticulin Promotes Folding of Functional Human Leukocyte Antigen Class I Molecules in Vitro. J. Biol. Chem. 279: 54210-54215 [Abstract] [Full Text]  
• Draenert, R., Le Gall, S., Pfafferott, K. J., Leslie, A. J., Chetty, P., Brander, C., Holmes, E. C., Chang, S.-C., Feeney, M. E., Addo, M. M., Ruiz, L., Ramduth, D., Jeena, P., Altfeld, M., Thomas, S., Tang, Y., Verrill, C. L., Dixon, C., Prado, J. G., Kiepiela, P., Martinez-Picado, J., Walker, B. D., Goulder, P. J.R. (2004). Immune Selection for Altered Antigen Processing Leads to Cytotoxic T Lymphocyte Escape in Chronic HIV-1 Infection. JEM 199: 905-915 [Abstract] [Full Text]  
• Peters, B., Bulik, S., Tampe, R., van Endert, P. M., Holzhutter, H.-G. (2003). Identifying MHC Class I Epitopes by Predicting the TAP Transport Efficiency of Epitope Precursors. J. Immunol. 171: 1741-1749 [Abstract] [Full Text]  
• Fruci, D., Lauvau, G., Saveanu, L., Amicosante, M., Butler, R. H., Polack, A., Ginhoux, F., Lemonnier, F., Firat, H., van Endert, P. M. (2003). Quantifying Recruitment of Cytosolic Peptides for HLA Class I Presentation: Impact of TAP Transport. J. Immunol. 170: 2977-2984 [Abstract] [Full Text]  
• Levy, F., Burri, L., Morel, S., Peitrequin, A.-L., Levy, N., Bachi, A., Hellman, U., Van den Eynde, B. J., Servis, C. (2002). The Final N-Terminal Trimming of a Subaminoterminal Proline-Containing HLA Class I-Restricted Antigenic Peptide in the Cytosol Is Mediated by Two Peptidases. J. Immunol. 169: 4161-4171 [Abstract] [Full Text]  
• Cohen, W. M., Bianco, A., Connan, F., Camoin, L., Dalod, M., Lauvau, G., Ferries, E., Culmann-Penciolelli, B., van Endert, P. M., Briand, J. P., Choppin, J., Guillet, J. G. (2002). Study of Antigen-Processing Steps Reveals Preferences Explaining Differential Biological Outcomes of Two HLA-A2-Restricted Immunodominant Epitopes from Human Immunodeficiency Virus Type 1. J. Virol. 76: 10219-10225 [Abstract] [Full Text]  
• Pentcheva, T., Edidin, M. (2001). Clustering of Peptide-Loaded MHC Class I Molecules for Endoplasmic Reticulum Export Imaged by Fluorescence Resonance Energy Transfer. J. Immunol. 166: 6625-6632 [Abstract] [Full Text]  
• Loirat, D., Lemonnier, F. A., Michel, M.-L. (2000). Multiepitopic HLA-A*0201-Restricted Immune Response Against Hepatitis B Surface Antigen After DNA-Based Immunization. J. Immunol. 165: 4748-4755 [Abstract] [Full Text]  
• Lucchiari-Hartz, M., van Endert, P. M., Lauvau, G., Maier, R., Meyerhans, A., Mann, D., Eichmann, K., Niedermann, G. (2000). Cytotoxic T Lymphocyte Epitopes of HIV-1 Nef: Generation of Multiple Definitive Major Histocompatibility Complex Class I Ligands by Proteasomes. JEM 191: 239-252 [Abstract] [Full Text]  
• Komlosh, A., Momburg, F., Weinschenk, T., Emmerich, N., Schild, H., Nadav, E., Shaked, I., Reiss, Y. (2001). A Role for a Novel Luminal Endoplasmic Reticulum Aminopeptidase in Final Trimming of 26 S Proteasome-generated Major Histocompatability Complex Class I Antigenic Peptides. J. Biol. Chem. 276: 30050-30056 [Abstract] [Full Text]  
• Menoret, A., Li, Z., Niswonger, M. L., Altmeyer, A., Srivastava, P. K. (2001). An Endoplasmic Reticulum Protein Implicated in Chaperoning Peptides to Major Histocompatibility of Class I Is an Aminopeptidase. J. Biol. Chem. 276: 33313-33318 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS