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

Charles L. Dulberger, Curtis P. McMurtrey, Angelique Hölzemer, Karlynn E. Neu, Victor Liu, Adriana M. Steinbach, Wilfredo F. Garcia-Beltran, Michael Sulak, Bana Jabri, Vincent J. Lynch, Marcus Altfeld, William H. Hildebrand, Erin J. Adams

Research output: Contribution to journalArticlepeer-review

89 Scopus citations


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. HLA-F can regulate immunity as an empty open conformer but whether or not HLA-F can present peptides is controversial. Dulberger et al. show that HLA-F has recently evolved an open-ended antigen-binding groove that facilitates presentation of uncharacteristically long peptides and that recognition of HLA-F by NKRs is tunable by peptide binding.

Original languageEnglish
Pages (from-to)1018-1029.e7
Issue number6
StatePublished - 20 Jun 2017
Externally publishedYes


  • HLA-F structure
  • KIR
  • LIR
  • MHC antigen presentation
  • MHC-I evolution
  • NK cell receptor
  • NK cell regulation


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