Natural HLA Class I Polymorphism Controls the Pathway of Antigen Presentation and Susceptibility to Viral Evasion Academic Article uri icon

abstract

  • HLA class I polymorphism creates diversity in epitope specificity and T cell repertoire. We show that HLA polymorphism also controls the choice of Ag presentation pathway. A single amino acid polymorphism that distinguishes HLA-B*4402 (Asp116) from B*4405 (Tyr116) permits B*4405 to constitutively acquire peptides without any detectable incorporation into the transporter associated with Ag presentation (TAP)-associated peptide loading complex even under conditions of extreme peptide starvation. This mode of peptide capture is less susceptible to viral interference than the conventional loading pathway used by HLA-B*4402 that involves assembly of class I molecules within the peptide loading complex. Thus, B*4402 and B*4405 are at opposite extremes of a natural spectrum in HLA class I dependence on the PLC for Ag presentation. These findings unveil a new layer of MHC polymorphism that affects the generic pathway of Ag loading, revealing an unsuspected evolutionary trade-off in selection for optimal HLA class I loading versus effective pathogen evasion.

authors

  • Zernich, Danielle
  • Purcell, Anthony W
  • Macdonald, Whitney A
  • Kjer-Nielsen, Lars
  • Ely, Lauren K
  • Laham, Nihay
  • Crockford, Tanya
  • Mifsud, Nicole A
  • Bharadwaj, Mandvi
  • Chang, Linus
  • Tait, Brian D
  • Holdsworth, Rhonda
  • Brooks, Andrew G
  • Bottomley, Stephen P
  • Beddoe, Travis
  • Peh, Chen Au
  • Rossjohn, Jamie
  • McCluskey, James

publication date

  • July 5, 2004