Open conformers of HLA-F are high-affinity ligands of the activating NK-cell receptor KIR3DS1

The activating NK-cell receptor KIR3DS1 has been implicated in the outcome of various human diseases, including delayed HIV-1 disease progression, yet a ligand that accounts for its biological effects remained unknown. We screened 100 HLA-I proteins and found that KIR3DS1 binds HLA-F, which was validated biochemically and functionally. Primary human KIR3DS1(+) NK cells degranulated and produced antiviral cytokines upon encountering HLA-F, and inhibited HIV-1 replication in vitro. CD4(+) T-cell activation triggered HLA-F transcription and expression and induced KIR3DS1 ligand expression. HIV-1 infection further increased HLA-F transcription, but decreased KIR3DS1 ligand expression, indicating an immune-evasion mechanism. Altogether, we established HLA-F as a ligand of KIR3DS1, and demonstrated cell-context-dependent expression of HLA-F that may explain the widespread influence of KIR3DS1 in human diseases.