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J. Biol. Chem., Vol. 280, Issue 25, 23900-23909, June 24, 2005
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High Resolution Structures of Highly Bulged Viral Epitopes Bound to Major Histocompatibility Complex Class I
IMPLICATIONS FOR T-CELL RECEPTOR ENGAGEMENT AND T-CELL IMMUNODOMINANCE*
¶***
¶¶||||
From the
Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia, the ||Cellular Immunology Laboratory, Queensland Institute of Medical Research, Brisbane 4029, Australia, and the **Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia
Although HLA class I alleles can bind epitopes up to 14 amino acids in length, little is known about the immunogenicity or the responding T-cell repertoire against such determinants. Here, we describe an HLA-B*3508-restricted cytotoxic T lymphocyte response to a 13-mer viral epitope (LPEPLPQGQLTAY). The rigid, centrally bulged epitope generated a biased T-cell response. Only the N-terminal face of the peptide bulge was critical for recognition by the dominant clonotype SB27. The SB27 public T-cell receptor (TcR) associated slowly onto the complex between the bulged peptide and the major histocompatibility complex, suggesting significant remodeling upon engagement. The broad antigen-binding cleft of HLA-B*3508 represents a critical feature for engagement of the public TcR, as the narrower binding cleft of HLA-B*3501LPEPLPQGQLTAY, which differs from HLA-B*3508 by a single amino acid polymorphism (Arg156 
Leu), interacted poorly with the dominant TcR. Biased TcR usage in this cytotoxic T lymphocyte response appears to reflect a dominant role of the prominent peptide·major histocompatibility complex class I surface.
Received for publication, March 21, 2005 , and in revised form, April 19, 2005.
The atomic coordinates and structure factors (codes 1ZHK and 1ZHL) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).
* This work was supported in part by the National Health and Medical Research Council, the Australian Research Council, the Juvenile Diabetes Research Foundation, and the Roche Organ Transplantation Research Foundation. 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.
The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure.
Both authors contributed equally to this work.
¶ Supported by an Australian Postgraduate Award scholarship.
*** Supported by a Peter Doherty fellowship from the National Health and Medical Research Council.
C. R. Roper Fellow of the University of Melbourne.
¶¶ Supported by a career development award from the National Health and Medical Research Council. To whom correspondence may be addressed. Tel.: 617-3845-3793; Fax: 617-3845-3510; E-mail: scottb{at}qimr.edu.au.
|||| Supported by a Wellcome Trust senior research fellowship in biomedical science in Australia. To whom correspondence may be addressed. Tel.: 613-9905-3736; Fax: 613-9905-4699; E-mail: Jamie.Rossjohn{at}med.monash.edu.au.
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