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

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SummaryEvidence 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.Graphical AbstractHighlightsThe crystal structure of HLA-F reveals a unique mode of peptide presentationLIR1 recognizes β2m-HLA-F via a docking strategy that precludes HLA-F OC recognitionPeptide-bound HLA-F and empty HLA-F OCs are recognized by distinct NKRsPeptide binding increases the proportion of leukocytes that stain with HLA-F tetramerHLA-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.

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