Antagonism of antiviral and allogeneic activity of a human public CTL clonotype by a single altered peptide ligand: implications for allograft rejection.
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 muM, 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.
Ely
Lauren K
LK
Department of Biochemistry and Molecular Biology, Protein Crystallography Unit, School of Biomedical Sciences, Monash University, Clayton, Australia.
Green
Katherine J
KJ
Beddoe
Travis
T
Clements
Craig S
CS
Miles
John J
JJ
Bottomley
Stephen P
SP
Zernich
Danielle
D
Kjer-Nielsen
Lars
L
Purcell
Anthony W
AW
McCluskey
James
J
Rossjohn
Jamie
J
Burrows
Scott R
SR
D000956:Antigens, Viral / Q000276:immunology* / Q000378:metabolism; D002461:Cell Line, Transformed; D002999:Clone Cells; D045142:Cross-Priming / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology* / Q000821:virology; D015235:HLA-B Antigens / Q000276:immunology / Q000378:metabolism; D059948:HLA-B44 Antigen; D015795:HLA-B8 Antigen / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D006207:Half-Life; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology / Q000378:metabolism; D007519:Isoantigens / Q000276:immunology*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology
D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; D059948:HLA-B44 Antigen; D015795:HLA-B8 Antigen; D016056:Immunodominant Epitopes; D007519:Isoantigens; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell