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

Archbold, Julia K., Macdonald, Whitney A., Gras, Stephanie, Ely, Lauren K., Miles, John J., Bell, Melissa J., Brennan, Rebekah M., Beddoe, Travis, Wilce, Matthew C.J., Clements, Craig S., Purcell, Anthony W., McCluskey, James, Burrows, Scott R., and Rossjohn, Jamie (2009) Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition. The Journal of Experimental Medicine, 206 (1). pp. 209-219.

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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.

Item ID: 45389
Item Type: Article (Research - C1)
ISSN: 1540-9538
Additional Information:

© 2009 Archbold et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

Funders: National Health and Medical Research Council of Australia (NHMRC), Australian Research Council (ARC)
Date Deposited: 06 Sep 2016 23:24
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110702 Applied Immunology (incl Antibody Engineering, Xenotransplantation and T-cell Therapies) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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