Supermotif peptide binding and degeneracy of MHC: peptide recognition in an EBV peptide-specific CTL response with highly restricted TCR usage.
We have investigated the presentation and CTL recognition of an HLA A*1101-restricted CTL peptide epitope AVFDRKSDAK (AVF)(3), derived from the EBV nuclear antigen (EBNA) 4, in the context of alleles belonging to the A3-supertype, A*0101, 0301, 1101, 3101, 3301, and 6801. The peptide binds to a A*6801 molecule as efficiently as to A*1101. The A*6801:AVF complex is recognized by some A*1101-restricted AVF- specific CTL clones. However, A*6801-positive (A*6801+) EBV-transformed lymphoblastoid cell lines (LCLs) are not killed by the same effectors. Furthermore, two A*6801+ donors did not mount an AVF-specific CTL response in vitro and lacked detectable AVF-specific effectors. Thus, this epitope is either subdominant, or non-immunogenic in the context of A*6801. These characteristics correlate with low stability of this MHC:peptide complex in living cells. We also demonstrate that a highly conserved AVF-specific TCR that dominates the AVF-specific CTL response in the majority of A*1101+ individuals recognizes the A*6801 molecule as a crossreactive alloantigen. Therefore, deletion of AVF-specific T cells may contribute to the non-immunogenicity or subdominance of the peptide in A*6801+ individuals.
Levitsky
V
V
Microbiology and Tumorbiology Center, Karolinska Institute, Stockholm, Sweden. victor.levitsky@mtc.ki.se
Liu
D
D
Southwood
S
S
Levitskaya
J
J
Sette
A
A
Masucci
M G
MG
D000483:Alleles; D020816:Amino Acid Motifs; D017951:Antigen Presentation; D002461:Cell Line, Transformed; D020031:Epstein-Barr Virus Infections / Q000276:immunology; D019309:Epstein-Barr Virus Nuclear Antigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D015234:HLA-A Antigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000737:chemistry / Q000276:immunology; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008285:Major Histocompatibility Complex / Q000276:immunology*; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D019309:Epstein-Barr Virus Nuclear Antigens; D015234:HLA-A Antigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell