Defining the structural basis for human alloantibody binding to human leukocyte antigen allele HLA-A11:01

• Published in: Nature communications Vol. 10; no. 1; p. 893
• Main Authors: Gu, Yue, Wong, Yee Hwa, Liew, Chong Wai, Chan, Conrad E. Z., Murali, Tanusya M., Yap, Jiawei, Too, Chien Tei, Purushotorman, Kiren, Hamidinia, Maryam, El Sahili, Abbas, Goh, Angeline T. H., Teo, Rachel Z. C., Wood, Kathryn J., Hanson, Brendon J., Gascoigne, Nicholas R. J., Lescar, Julien, Vathsala, Anantharaman, MacAry, Paul A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21-02-2019; Nature Publishing Group; Nature Portfolio
• Subjects: 101/1; 13/31; 631/250/1619/554/1775; 631/250/1854/2812; 631/250/21/324/1509; 631/535/1266; 82/80; 82/81; Alloantibodies; Amino Acid Sequence; Antibodies; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - genetics; Antibodies, Monoclonal - metabolism; Antibody Specificity; Antigen-Antibody Complex - chemistry; Antigen-Antibody Complex - genetics; Antigen-Antibody Complex - metabolism; Antigenic determinants; Antigens; Binding; Binding Sites, Antibody - genetics; CD8 antigen; Crystallography, X-Ray; Determinants; Epitopes; Epitopes - chemistry; Epitopes - genetics; Epitopes - metabolism; HLA-A11 Antigen - chemistry; HLA-A11 Antigen - genetics; HLA-A11 Antigen - metabolism; Humanities and Social Sciences; Humans; Immunoglobulin G - chemistry; Immunoglobulin G - genetics; Immunoglobulin G - metabolism; Isoantibodies - chemistry; Isoantibodies - genetics; Isoantibodies - metabolism; Killer cell immunoglobulin-like receptors; Leukocytes; Lymphocytes T; Models, Molecular; multidisciplinary; Peptide Library; Protein Conformation; Receptors; Science; Science (multidisciplinary); T cell receptors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-08790-1

Our understanding of the conformational and electrostatic determinants that underlie targeting of human leukocyte antigens (HLA) by anti-HLA alloantibodies is principally based upon in silico modelling. Here we provide a biochemical/biophysical and functional characterization of a human monoclonal alloantibody specific for a common HLA type, HLA-A*11:01. We present a 2.4 Å resolution map of the binding interface of this antibody on HLA-A*11:01 and compare the structural determinants with those utilized by T-cell receptor (TCR), killer-cell immunoglobulin-like receptor (KIR) and CD8 on the same molecule. These data provide a mechanistic insight into the paratope−epitope relationship between an alloantibody and its target HLA molecule in a biological context where other immune receptors are concomitantly engaged. This has important implications for our interpretation of serologic binding patterns of anti-HLA antibodies in sensitized individuals and thus, for the biology of human alloresponses.
Anti-human leukocyte antigen (HLA) antibodies are important mediators of alloresponses, but structural insights on antibody:HLA interaction are still lacking. Here the authors provide a 2.4 Å structure of antibody:HLA complex, and also analyse HLA features important for other HLA-interacting molecules, to enhance our understanding of alloimmunity.