The same natural ligand is involved in allorecognition of multiple HLA-B27 subtypes by a single T cell clone: role of peptide and the MHC molecule in alloreactivity.
The human alloreactive CTL clone 27S69, raised against B*2705, cross-reacts with B*2702 and B*2703, but not with B*2701, B*2704, B*2706, or B*2710. Its natural epitope was identified by electrospray/ion trap mass spectrometry, as the proteasome-derived RRFFPYYV octamer. This is the first HLA-B27 ligand shown to be immunogenic in alloreactivity. The RRFFPYYVY nonamer, also found in the B*2705-bound peptide pool, was recognized much less efficiently, demonstrating that an alloreactive CTL distinguishes between very similar natural ligands. Molecular modeling suggested that this was due to the different conformation of each peptide in complex with B*2705. B*2702- and B*2703-RMA-S cells were lysed by CTL 27S69 when sensitized with the octamer, demonstrating that cross-reaction with these subtypes is through recognition of the same peptide as in B*2705. B*2704-, B*2706-, and B*2710-RMA-S cells were not sensitized for lysis, in spite of efficient binding of the octamer, indicating that polymorphism in these subtypes directly impairs allorecognition. B*2701-RMA-S and -C1R cells were sensitized for lysis by the octamer, suggesting lack of the endogenous peptide epitope on this subtype. Absence of the octamer in the B*2701-bound peptide pool further suggested that B*2701 polymorphism impairs the generation of this peptide.
Paradela
A
A
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, Facultad de Ciencias, Spain.
García-Peydró
M
M
Vázquez
J
J
Rognan
D
D
López de Castro
J A
JA
D000483:Alleles; D017951:Antigen Presentation; D001665:Binding Sites / Q000276:immunology; D002851:Chromatography, High Pressure Liquid; D002999:Clone Cells; D000939:Epitopes / Q000302:isolation & purification / Q000378:metabolism; D015796:HLA-B27 Antigen / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009842:Oligopeptides / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism*
D000939:Epitopes; D015796:HLA-B27 Antigen; D008024:Ligands; D009842:Oligopeptides