Human Leukocyte Antigen F Presents Peptides and Regulates Immunity through Interactions with NK Cell Receptors

  • Immunity. 2017 Jun 20;46(6):1018-1029.e7. doi: 10.1016/j.immuni.2017.06.002.
Charles L Dulberger  1 ,  Curtis P McMurtrey  2 ,  Angelique Hölzemer  3 ,  Karlynn E Neu  4 ,  Victor Liu  1 ,  Adriana M Steinbach  1 ,  Wilfredo F Garcia-Beltran  5 ,  Michael Sulak  6 ,  Bana Jabri  7 ,  Vincent J Lynch  6 ,  Marcus Altfeld  8 ,  William H Hildebrand  2 ,  Erin J Adams  9
Affiliations
  • 1. Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA.
  • 2. Department of Microbiology and Immunology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
  • 3. Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg 20251, Germany; First Department of Internal Medicine, Infectious Disease Unit, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany; German Center for Infection Research (DZIF), Hamburg 20246, Germany.
  • 4. Committee on Immunology, University of Chicago, Chicago, IL 60637, USA.
  • 5. Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
  • 6. Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
  • 7. Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA; Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
  • 8. Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg 20251, Germany.
  • 9. Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA. Electronic address: [email protected].
PMID: 28636952 DOI: 10.1016/j.immuni.2017.06.002
Abstract

Evidence is mounting that the major histocompatibility complex (MHC) molecule HLA-F (human leukocyte antigen F) regulates the immune system in pregnancy, Infection, and autoimmunity by signaling through NK cell receptors (NKRs). We present structural, biochemical, and evolutionary analyses demonstrating that HLA-F presents Peptides of unconventional length dictated by a newly arisen mutation (R62W) that has produced an open-ended groove accommodating particularly long Peptides. Compared to empty HLA-F open conformers (OCs), HLA-F tetramers bound with human-derived Peptides differentially stained leukocytes, suggesting peptide-dependent engagement. Our in vitro studies confirm that NKRs differentiate between peptide-bound and peptide-free HLA-F. The complex structure of peptide-loaded β2m-HLA-F bound to the inhibitory LIR1 revealed similarities to high-affinity recognition of the viral MHC-I mimic UL18 and a docking strategy that relies on contacts with HLA-F as well as β2m, thus precluding binding to HLA-F OCs. These findings provide a biochemical framework to understand how HLA-F could regulate immunity via interactions with NKRs.

Keywords
HLA-F structure; KIR; LIR; MHC antigen presentation; MHC-I evolution; NK cell receptor; NK cell regulation.