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J. Biol. Chem., Vol. 281, Issue 45, 34324-34332, November 10, 2006

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Alloreactivity between Disparate Cognate and Allogeneic pMHC-I Complexes Is the Result of Highly Focused, Peptide-dependent Structural Mimicry^*

Julia K. Archbold¹², Whitney A. Macdonald¹³, John J. Miles², Rebekah M. Brennan, Lars Kjer-Nielsen^¶, James McCluskey^¶, Scott R. Burrows⁴⁵, and Jamie Rossjohn, An Australian Research Council Federation Fellow⁶

From the Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia, Cellular Immunology Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia, and ^¶Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia

Our understanding of the molecular mechanisms of T cell alloreactivity remains limited by the lack of systems for which both the T cell receptor allo- and cognate ligand are known. Here we provide evidence that a single alloreactive T cell receptor interacts with analogous structural regions of its cognate ligand, HLA-B^*0801^FLRGRAYGL, as its allogeneic ligand, HLA-B^*3501^KPIVVLHGY. The crystal structures of the binary peptide-major histocompatibility complexes show marked differences in the conformation of the heavy chains as well as the bound peptides. Nevertheless, both epitopes possess a prominent solvent-exposed aromatic residue at position 7 flanked by a small glycine at position 8 of the peptide determinant. Moreover, regions of close structural homology between the heavy chains of HLA B8 and HLA B35 coincided with regions that have previously been implicated in "hot spots" of T cell receptor recognition. The avidity of this human T cell receptor was also comparable for the allo- and cognate ligand, consistent with the modes of T cell receptor binding being broadly similar for these complexes. Collectively, it appears that highly focused structural mimicry against a diverse structural background provides a basis for the observed alloreactivity in this system. This cross-reactivity underpins the T cell degeneracy inherent in the limited mature T cell repertoire that must respond to a vast diversity of microbial antigens.

Received for publication, July 17, 2006 , and in revised form, September 5, 2006.

The atomic coordinates and structure factors (code 2H6P) 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 grants from the Australian Research Council and the National Health and Medical Research Council, Australia. 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 supplemental Fig. 1.

¹ These authors contributed equally.

² Supported by Dora Lush National Health and Medical Research Council Scholarships.

³ Supported by a National Health and Medical Research Council Peter Doherty Training Fellowship.

⁴ A recipient of a National Health and Medical Research Council Career Development Award.

⁵ To whom correspondence may be addressed. Tel.: 61-7-3845-3793; Fax: 61-7-3362-0106; E-mail: Scott.Burrows{at}qimr.edu.au. ⁶ To whom correspondence may be addressed. Tel.: 61-9905-3736; Fax: 61-9905-4699; E-mail: jamie.rossjohn{at}med.monash.edu.au.

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