TCR alpha genes direct MHC restriction in the potent human T cell response to a class I-bound viral epitope.
The underlying generic properties of alphabeta 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 beta-chain usage in both HLA-B*3501+ and HLA-B*3508+ individuals; however, this conserved TRBV9+ beta-chain was associated with distinct TCR alpha-chains depending upon the HLA-B*35 allele expressed by the virus-exposed host. Functional assays confirmed that TCR alpha-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 alpha-chain usage is shown to play a critical role in controlling MHC restriction between closely related allomorphs.
Miles
John J
JJ
Cellular Immunology Laboratory, Queensland Institute of Medical Research, Brisbane, Australia.
Borg
Natalie A
NA
Brennan
Rebekah M
RM
Tynan
Fleur E
FE
Kjer-Nielsen
Lars
L
Silins
Sharon L
SL
Bell
Melissa J
MJ
Burrows
Jacqueline M
JM
McCluskey
James
J
Rossjohn
Jamie
J
Burrows
Scott R
SR
D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000235:genetics; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000276:immunology* / Q000378:metabolism; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015235:HLA-B Antigens / Q000378:metabolism; D015797:HLA-B35 Antigen; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism* / Q000821:virology*
D018984:Epitopes, T-Lymphocyte; D019309:Epstein-Barr Virus Nuclear Antigens; D006680:HLA Antigens; D015235:HLA-B Antigens; C500431:HLA-B*35:01 antigen; D015797:HLA-B35 Antigen; D015395:Histocompatibility Antigens Class I; D021122:Protein Subunits; D016693:Receptors, Antigen, T-Cell, alpha-beta; C417029:EBV-encoded nuclear antigen 1