The immunogenetic diversity of a cohort of northern Indigenous Australians revealed substantial genetic variation that has the potential to diversify NK cell responses to viral infections. Killer cell immunoglobulin-like receptors (KIRs) have an essential role in the control of natural killer (NK) cells, mainly by interacting with major histocompatibility complex (MHC) class I molecules. Among the multiple allotypes of HLA class I, A*24:02, which is highly prevalent in Oceania, associates with poor influenza disease prognosis. HLA-A*24:02 interacts with the highly polymorphic NK cell inhibiting receptor, KIR3DL1, through possessing a ‘Bw4’ sequence motif.
A striking feature of the Indigenous and Maori KIR3DL1 allotypes (KIR3DL1*114 and *086, respectively) is their possession of phenylalanine at position 166, instead of a leucine. To understand how the substitution of a leucine with a phenylalanine at residue 166 impact Bw4+ HLA binding, structural and function studies were performed. Together, our results suggest a trend of increased affinity for the Indigenous and Maori KIR3DL1 to HLA-A*24:02 presenting viral peptides, and these differences are likely to be attributed to the L166F substitution. To confirm the observed enhanced recognition effect of L166F substitution on peptide and HLA allotype recognition, we determined the crystal structures of KIR3DL1*001 and KIR3DL1*114 bound to the HLA-A*24:02 TW9 peptide complex. Overall, from the analysis of our structures, Phe166 enhances the interaction affinity via an increase in the hydrophobic surface area at both the peptide and HLA interfaces. Furthermore, our observations suggest evidence both for historical and ongoing selection for specific HLA and KIR allotypes in the Indigenous Australian population.