Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition Academic Article uri icon

abstract

  • Human leukocyte antigen (HLA) gene polymorphism plays a critical role in protective immunity, disease susceptibility, autoimmunity, and drug hypersensitivity, yet the basis of how HLA polymorphism influences T cell receptor (TCR) recognition is unclear. We examined how a natural micropolymorphism in HLA-B44, an important and large HLA allelic family, affected antigen recognition. T cell-mediated immunity to an Epstein-Barr virus determinant (EENLLDFVRF) is enhanced when HLA-B*4405 was the presenting allotype compared with HLA-B*4402 or HLA-B*4403, each of which differ by just one amino acid. The micropolymorphism in these HLA-B44 allotypes altered the mode of binding and dynamics of the bound viral epitope. The structure of the TCR-HLA-B*4405(EENLLDFVRF) complex revealed that peptide flexibility was a critical parameter in enabling preferential engagement with HLA-B*4405 in comparison to HLA-B*4402/03. Accordingly, major histocompatibility complex (MHC) polymorphism can alter the dynamics of the peptide-MHC landscape, resulting in fine-tuning of T cell responses between closely related allotypes.

authors

  • Archbold, Julia K
  • Macdonald, Whitney A
  • Gras, Stephanie
  • Ely, Lauren K
  • Miles, John J
  • Bell, Melissa J
  • Brennan, Rebekah M
  • Beddoe, Travis
  • Wilce, Matthew CJ
  • Clements, Craig S
  • Purcell, Anthony W
  • McCluskey, James
  • Burrows, Scott R
  • Rossjohn, Jamie

publication date

  • January 16, 2009

has subject area