HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ely, L. K. Articles by Burrows, S. R. Search for Related Content PubMed PubMed Citation Articles by Ely, L. K. Articles by Burrows, S. R.

Antagonism of Antiviral and Allogeneic Activity of a Human Public CTL Clonotype by a Single Altered Peptide Ligand: Implications for Allograft Rejection ¹

Lauren K. Ely^*, Katherine J. Green, Travis Beddoe^*, Craig S. Clements^*, John J. Miles, Stephen P. Bottomley^*, Danielle Zernich, Lars Kjer-Nielsen, Anthony W. Purcell, James McCluskey, Jamie Rossjohn^2,* and Scott R. Burrows^2,

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

Alloreactive T lymphocytes are central mediators of graft-versus-host disease and allograft rejection. A public CTL clonotype with specificity for the alloantigens HLA-B*4402 and B*4405 is often expanded to large numbers in healthy HLA-B*0801⁺ individuals, driven by cross-reactive stimulation with the common, persistent herpesvirus EBV. Since such alloreactive memory CTL expansions have the potential to influence transplantation outcome, altered peptide ligands (APLs) of the target HLA-B*0801-binding EBV peptide, FLRGRAYGL, were screened as specific antagonists for this immunodominant clonotype. One APL, FLRGRFYGL, exerted powerful antagonism of a prototypic T cell clone expressing this immunodominant TCR when costimulated with target cells presenting HLA-B*0801^FLRGRAYGL. Significantly, this APL also reduced the lysis of allogeneic target cells expressing HLA-B*4402 by up to 99%. The affinities of the agonist and antagonist complexes for the public TCR, measured using solution and solid-phase assays, were 8 and 138 µM, respectively. Surprisingly, the half-life of the agonist and antagonist complexes was similar, yet the association rate for the antagonist complex was significantly slower. These observations were further supported by structural studies that suggested a large conformational hurdle was required to ligate the immunodominant TCR to the HLA-B*0801 antagonist complex. By defining an antagonist APL against an immunodominant alloreactive TCR, these findings raise the prospect of exploiting such peptides to inhibit clinical alloreactivity, particularly against clonal T cell expansions that react with alloantigens.

This article has been cited by other articles:

				V. Venturi, H. Y. Chin, D. A. Price, D. C. Douek, and M. P. Davenport The Role of Production Frequency in the Sharing of Simian Immunodeficiency Virus-Specific CD8+ TCRs between Macaques J. Immunol., August 15, 2008; 181(4): 2597 - 2609. [Abstract] [Full Text] [PDF]

				L. K. Ely, T. Beddoe, C. S. Clements, J. M. Matthews, A. W. Purcell, L. Kjer-Nielsen, J. McCluskey, and J. Rossjohn Disparate thermodynamics governing T cell receptor-MHC-I interactions implicate extrinsic factors in guiding MHC restriction PNAS, April 25, 2006; 103(17): 6641 - 6646. [Abstract] [Full Text] [PDF]

				B. Koehn, S. Gangappa, J. D. Miller, R. Ahmed, and C. P. Larsen Patients, pathogens, and protective immunity: the relevance of virus-induced alloreactivity in transplantation. J. Immunol., March 1, 2006; 176(5): 2691 - 2696. [Abstract] [Full Text] [PDF]