Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding

  • Nat Commun. 2018 Aug 7;9(1):3137. doi: 10.1038/s41467-018-05459-z.
Lucy C Walters  1 ,  Karl Harlos  2 ,  Simon Brackenridge  1 ,  Daniel Rozbesky  2 ,  Jordan R Barrett  1 ,  Vitul Jain  2 ,  Thomas S Walter  2 ,  Chris A O'Callaghan  3 ,  Persephone Borrow  1 ,  Mireille Toebes  4 ,  Scott G Hansen  5 ,  Jonah B Sacha  5 ,  Shaheed Abdulhaqq  5 ,  Justin M Greene  5 ,  Klaus Früh  5 ,  Emily Marshall  5 ,  Louis J Picker  5 ,  E Yvonne Jones  2 ,  Andrew J McMichael  6 ,  Geraldine M Gillespie  7
Affiliations
  • 1. Nuffield Department of Medicine Research Building, Roosevelt Drive, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK.
  • 2. Division of Structural Biology, Wellcome Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, OX3 7BN, UK.
  • 3. Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, OX3 7BN, UK.
  • 4. Department Molecular Oncology and Immunology, B6 Plesmanlaan 121, Amsterdam, 1066CX, The Netherlands.
  • 5. Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, 97006, USA.
  • 6. Nuffield Department of Medicine Research Building, Roosevelt Drive, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK. [email protected].
  • 7. Nuffield Department of Medicine Research Building, Roosevelt Drive, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK. [email protected].
PMID: 30087334 DOI: 10.1038/s41467-018-05459-z
Abstract

Through major histocompatibility complex class Ia leader sequence-derived (VL9) peptide binding and CD94/NKG2 receptor engagement, human leucocyte antigen E (HLA-E) reports cellular health to NK cells. Previous studies demonstrated a strong bias for VL9 binding by HLA-E, a preference subsequently supported by structural analyses. However, Mycobacteria tuberculosis (Mtb) Infection and Rhesus cytomegalovirus-vectored SIV vaccinations revealed contexts where HLA-E and the rhesus homologue, Mamu-E, presented diverse pathogen-derived peptides to CD8+ T cells, respectively. Here we present crystal structures of HLA-E in complex with HIV and Mtb-derived peptides. We show that despite the presence of preferred primary anchor residues, HLA-E-bound peptides can adopt alternative conformations within the peptide binding groove. Furthermore, combined structural and mutagenesis analyses illustrate a greater tolerance for hydrophobic and polar residues in the primary pockets than previously appreciated. Finally, biochemical studies reveal HLA-E peptide binding and exchange characteristics with potential relevance to its alternative antigen presenting function in vivo.