Home | Help | Feedback | Subscriptions | Archive | Search | Latest Articles

This Article Full Text Full Text (PDF, 410K) PPT slides of all figures Supplemental Material Index Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zernich, D. Articles by McCluskey, J. Search for Related Content PubMed PubMed Citation Articles by Zernich, D. Articles by McCluskey, J. Social Bookmarking                            What's this?

Natural HLA Class I Polymorphism Controls the Pathway of Antigen Presentation and Susceptibility to Viral Evasion

Danielle Zernich¹, Anthony W. Purcell¹, Whitney A. Macdonald¹, Lars Kjer-Nielsen¹, Lauren K. Ely², Nihay Laham¹, Tanya Crockford¹, Nicole A. Mifsud¹, Mandvi Bharadwaj¹, Linus Chang¹, Brian D. Tait³, Rhonda Holdsworth³, Andrew G. Brooks¹, Stephen P. Bottomley², Travis Beddoe², Chen Au Peh⁴, Jamie Rossjohn², and James McCluskey¹

¹ Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia
² The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia
³ Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood Service, South Melbourne, Victoria 3205, Australia
⁴ Renal Unit, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia

Address correspondence to James McCluskey, Dept. of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria 3010, Australia. Phone: 61-3-83445709; Fax: 61-3-93473226; email: jamesm1{at}unimelb.edu.au; or Jamie Rossjohn, Dept. of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia. Phone: 61-3-99053736; Fax: 61-3-99054699; email: Jamie.Rossjohn{at}med.monash.edu.au

HLA class I polymorphism creates diversity in epitope specificity and T cell repertoire. We show that HLA polymorphism also controls the choice of Ag presentation pathway. A single amino acid polymorphism that distinguishes HLA-B*4402 (Asp116) from B*4405 (Tyr116) permits B*4405 to constitutively acquire peptides without any detectable incorporation into the transporter associated with Ag presentation (TAP)-associated peptide loading complex even under conditions of extreme peptide starvation. This mode of peptide capture is less susceptible to viral interference than the conventional loading pathway used by HLA-B*4402 that involves assembly of class I molecules within the peptide loading complex. Thus, B*4402 and B*4405 are at opposite extremes of a natural spectrum in HLA class I dependence on the PLC for Ag presentation. These findings unveil a new layer of MHC polymorphism that affects the generic pathway of Ag loading, revealing an unsuspected evolutionary trade-off in selection for optimal HLA class I loading versus effective pathogen evasion.

Key Words: HLA • polymorphism • Ag presentation • tapasin • immune evasion

D. Zernich and A.W. Purcell contributed equally to this work.

The online version of this article contains supplemental material.

Abbreviations used in this paper: Endo H, endoglycosidase H; PLC, peptide loading complex; TAP, transporter associated with Ag presentation.

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

This article has been cited by other articles:

• Archbold, J. K., Macdonald, W. A., Gras, S., Ely, L. K., Miles, J. J., Bell, M. J., Brennan, R. M., Beddoe, T., Wilce, M. C.J., Clements, C. S., Purcell, A. W., McCluskey, J., Burrows, S. R., Rossjohn, J. (2009). Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition. JEM 206: 209-219 [Abstract] [Full Text]  
• Escobar, H., Crockett, D. K., Reyes-Vargas, E., Baena, A., Rockwood, A. L., Jensen, P. E., Delgado, J. C. (2008). Large Scale Mass Spectrometric Profiling of Peptides Eluted from HLA Molecules Reveals N-Terminal-Extended Peptide Motifs. J. Immunol. 181: 4874-4882 [Abstract] [Full Text]  
• Garstka, M., Borchert, B., Al-Balushi, M., Praveen, P., Kuhl, N., Majoul, I., Duden, R., Springer, S. (2007). Peptide-receptive Major Histocompatibility Complex Class I Molecules Cycle between Endoplasmic Reticulum and cis-Golgi in Wild-type Lymphocytes. J. Biol. Chem. 282: 30680-30690 [Abstract] [Full Text]  
• Leslie, A., Price, D. A., Mkhize, P., Bishop, K., Rathod, A., Day, C., Crawford, H., Honeyborne, I., Asher, T. E., Luzzi, G., Edwards, A., Rosseau, C. M., Mullins, J. I., Tudor-Williams, G., Novelli, V., Brander, C., Douek, D. C., Kiepiela, P., Walker, B. D., Goulder, P. J. R. (2006). Differential Selection Pressure Exerted on HIV by CTL Targeting Identical Epitopes but Restricted by Distinct HLA Alleles from the Same HLA Supertype. J. Immunol. 177: 4699-4708 [Abstract] [Full Text]  
• Thammavongsa, V., Raghuraman, G., Filzen, T. M., Collins, K. L., Raghavan, M. (2006). HLA-B44 Polymorphisms at Position 116 of the Heavy Chain Influence TAP Complex Binding via an Effect on Peptide Occupancy.. J. Immunol. 177: 3150-3161 [Abstract] [Full Text]  
• Leonhardt, R. M., Keusekotten, K., Bekpen, C., Knittler, M. R. (2005). Critical Role for the Tapasin-Docking Site of TAP2 in the Functional Integrity of the MHC Class I-Peptide-Loading Complex. J. Immunol. 175: 5104-5114 [Abstract] [Full Text]  
• Shao, H., Peng, Y., Liao, T., Wang, M., Song, M., Kaplan, H. J., Sun, D. (2005). A Shared Epitope of the Interphotoreceptor Retinoid-Binding Protein Recognized by the CD4+ and CD8+ Autoreactive T Cells. J. Immunol. 175: 1851-1857 [Abstract] [Full Text]  
• Fiorillo, M. T., Ruckert, C., Hulsmeyer, M., Sorrentino, R., Saenger, W., Ziegler, A., Uchanska-Ziegler, B. (2005). Allele-dependent Similarity between Viral and Self-peptide Presentation by HLA-B27 Subtypes. J. Biol. Chem. 280: 2962-2971 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search