Peptide presentation to an alloreactive CTL clone is modulated through multiple mechanisms involving polymorphic and conserved residues in HLA-B27.
This study addressed the mechanisms by which HLA class I polymorphism modulates allorecognition. CTL 27S69 is an alloreactive clone raised against HLA-B*2705, with a known peptide epitope. This CTL cross-reacts with B*2702, which differs from B*2705 in the D77N, T80I, and L81A changes, but not with B*2701, which has D74Y, D77N, and L81A changes. To explain this differential recognition, B*2705 mutants mimicking subtype changes were used. The A81 mutant was not recognized, despite binding the natural epitope in vivo, suggesting that, when bound to this mutant, this peptide adopts an inappropriate conformation. The N77 and I80 mutations restored recognition in the N77A81 or I80A81 mutants. These compensatory effects explain the cross-reaction with B*2702. The Y74 and the Y74N77 mutants were weakly recognized or not recognized by CTL 27S69. This correlated with the absence or marginal presence of the peptide epitope in the Y74N77-bound pool. As with B*2701, exogenous addition of the peptide epitope sensitized Y74 and Y74N77 targets for lysis, indicating that failure to cross-react with B*2701 or these mutants was due to poor binding of the peptide in vivo and not to inappropriate presentation. The abrogating effect of Y74 was critically dependent upon the K70 residue, conserved among subtypes, as demonstrated with mutants at this position. Thus, HLA polymorphism affects allorecognition by modulating peptide binding or the conformation of bound peptides. Compensatory mutations and indirect effects of a polymorphic residue on residues conserved play a critical role.
García-Peydró
M
M
Centro de Biología Molecular Severo Ochoa, (Consejo Superior de Investigaciones Cientificas, Universidad Autónoma de Madrid, Facultad de Ciencias, Madrid, Spain.
Paradela
A
A
Lamas
J R
JR
López De Castro
J A
JA
D000595:Amino Acid Sequence; D017951:Antigen Presentation; D002999:Clone Cells; D017124:Conserved Sequence; D000939:Epitopes; D015796:HLA-B27 Antigen / Q000235:genetics*; D009842:Oligopeptides / Q000276:immunology* / Q000378:metabolism; D011110:Polymorphism, Genetic; D011485:Protein Binding; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000939:Epitopes; D015796:HLA-B27 Antigen; D009842:Oligopeptides