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TCR Genes Direct MHC Restriction in the Potent Human T Cell Response to a Class I-Bound Viral Epitope¹

John J. Miles^2,*,, Natalie A. Borg^2,, Rebekah M. Brennan^*, Fleur E. Tynan, Lars Kjer-Nielsen, Sharon L. Silins^*, Melissa J. Bell^*, Jacqueline M. Burrows^*, James McCluskey, Jamie Rossjohn^3, and Scott R. Burrows^3,*

^* Cellular Immunology Laboratory, Queensland Institute of Medical Research, Brisbane, Australia; School of Population Health, University of Queensland, Brisbane, Australia; The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Australia; and Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia

The underlying generic properties of β TCRs that control MHC restriction remain largely unresolved. To investigate MHC restriction, we have examined the CTL response to a viral epitope that binds promiscuously to two human leukocyte Ags (HLAs) that differ by a single amino acid at position 156. Individuals expressing either HLA-B*3501 (¹⁵⁶Leucine) or HLA-B*3508 (¹⁵⁶Arginine) showed a potent CTL response to the ⁴⁰⁷HPVGEADYFEY⁴¹⁷ epitope from EBV. Interestingly, the response was characterized by highly restricted TCR β-chain usage in both HLA-B*3501⁺ and HLA-B*3508⁺ individuals; however, this conserved TRBV9⁺ β-chain was associated with distinct TCR -chains depending upon the HLA-B*35 allele expressed by the virus-exposed host. Functional assays confirmed that TCR -chain usage determined the HLA restriction of the CTLs. Structural studies revealed significant differences in the mobility of the peptide when bound to HLA-B*3501 or HLA-B*3508. In HLA-B*3501, the bulged section of the peptide was disordered, whereas in HLA-B*3508 the bulged epitope adopted an ordered conformation. Collectively, these data demonstrate not only that mobile MHC-bound peptides can be highly immunogenic but can also stimulate an extremely biased TCR repertoire. In addition, TCR -chain usage is shown to play a critical role in controlling MHC restriction between closely related allomorphs.

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 This work was supported by grants from the Australian National Health and Medical Research Council (NHMRC), the Roche Organ Transplantation Research Fund, the Juvenile Diabetes Research Foundation, and the Australian Research Council. N.A.B. is a recipient of an NHMRC Peter Doherty Research Fellowship, S.R.B. is a recipient of an NHMRC Career Development award, and J.R. is an Australian Research Council Federation Fellow.

² J.J.M. and N.A.B. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Scott R. Burrows, Cellular Immunology Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia. E-mail address: Scott.Burrows{at}qimr.edu.au or Prof. Jamie Rossjohn, The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia, E-mail: Jamie.Rossjohn{at}med.monash.edu.au

⁴ Abbreviations used in this paper: pMHC-I, peptide-MHC complex class I; HPVG, 11-mer EBV peptide HPVGEADYFEY; TRBV, TCR β-chain variable.

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