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Title: Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition

Journal Article · · J. Exp. Med.
DOI:https://doi.org/10.1084/jem.20082136· OSTI ID:1005731

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*4405EENLLDFVRF 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.

Research Organization:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE
OSTI ID:
1005731
Journal Information:
J. Exp. Med., Vol. 206, Issue (1) ; 01, 2009; ISSN 0022-1007
Country of Publication:
United States
Language:
ENGLISH