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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 Brooks, Andrew G. Vivian, Julian P.
Pymm, Phillip
Saunders, Philippa M.
Anand, Sushma
MacLachlan, Bruce J.
Faoro, Camilla
Hitchen, Corinne
Rossjohn, Jamie
Brooks, Andrew G.
Vivian, Julian P.
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.
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Date
2024
Type
Journal article
Journal
Journal of Immunology
Book
Volume
213
Issue
6
Page Range
876-885
Article Number
ACU Department
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All rights reserved
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Copyright © 2024 by The American Association of Immunologists, Inc.