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Evidence is mounting that HLA-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 in the antigen-binding cleft (R62W) that has produced an open-ended groove that accommodates particularly long peptides. Compared to empty HLA-F open conformers (OC), HLA-F tetramers bound with human-derived peptides differentially stain leukocytes suggesting peptide- dependent engagement. Our binding studies and functional assays confirm that NKRs differentiate between peptide-bound and peptide-free HLA-F OC. The complex structure of peptide-loaded β2m-HLA-F bound to the inhibitory LIR1 reveals similarities to high- affinity UL18 recognition and a docking strategy that relies on contacts with the HLA-F heavy chain as well as β2m, precluding binding to HLA-F OC. These findings provide the biochemical framework for how HLA-F regulates immunity via interactions with NKRs. ,Supplementary Table 2.2, which contains the peptide sequences eluted from HLA-F produced in HEK293T cells, can be found online


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