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
|Pages (from-to)||209 - 219|
|Number of pages||11|
|Journal|| Journal of Experimental Medicine|
|Publication status||Published - 2009|
Archbold, J. K., Macdonald, W. A., Gras, S.
, Ely, L. K., Miles, J. J., Bell, M. J., Brennan, R. M., Beddoe, T. C., Wilce, M. C. J.
, Clements, C. S., Purcell, A. W.
, McCluskey, J., Burrows, S. R., & Rossjohn, J.
(2009). Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition
. Journal of Experimental Medicine
(1), 209 - 219.