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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology
  • Cytomegalovirus
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes*
  • HEK293 Cells
  • Histocompatibility Antigens Class I / immunology*
  • Humans
  • Killer Cells, Natural / immunology
  • Macaca mulatta
  • Mycobacterium tuberculosis
  • Peptides / immunology*
  • Protein Binding
  • Protein Conformation
  • Simian Immunodeficiency Virus / immunology

Substances

  • Epitopes
  • HLA-E antigen
  • Histocompatibility Antigens Class I
  • Peptides