The structural basis for recognition of human leukocyte antigen class I molecules by the Pan-HLA antibody w6/32

Pymm, Phillip, Saunders, Philippa M., Anand, Sushma, MacLachlan, Bruce J., Faoro, Camilla, Hitchen, Corinne, Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, Brooks, Andrew G. and Vivian, Julian P. 2024. The structural basis for recognition of human leukocyte antigen class I molecules by the Pan-HLA antibody w6/32. The Journal of Immunology 213 (6) , pp. 876-885. 10.4049/jimmunol.2400328

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Abstract

The central immunological role of HLA class I (HLA-I) in presenting peptide Ags to cellular components of the immune system has been the focus of intense study for >60 y. A confounding factor in the study of HLA-I has been the extreme polymorphism of these molecules. The mAb W6/32 has been a fundamental reagent bypassing the issue of polymorphism by recognizing an epitope that is conserved across diverse HLA-I allotypes. However, despite the widespread use of W6/32, the epitope of this Ab has not been definitively mapped. In this study, we present the crystal structure of the Fab fragment of W6/32 in complex with peptide–HLA-B*27:05. W6/32 bound to HLA-B*27:05 beneath the Ag-binding groove, recognizing a discontinuous epitope comprised of the α1, α2, and α3 domains of HLA-I and β2-microglobulin. The epitope comprises a region of low polymorphism reflecting the pan–HLA-I nature of the binding. Notably, the W6/32 epitope neither overlaps the HLA-I binding sites of either T cell Ag receptors or killer cell Ig-like receptors. However, it does coincide with the binding sites for leukocyte Ig-like receptors and CD8 coreceptors. Consistent with this, the use of W6/32 to block the interaction of NK cells with HLA-I only weakly impaired inhibition mediated by KIR3DL1, but impacted HLA-LILR recognition.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	American Association of Immunologists
ISSN:	0022-1767
Date of Acceptance:	9 July 2024
Last Modified:	16 Jan 2025 11:45
URI:	https://orca.cardiff.ac.uk/id/eprint/175320

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