First Nations people are at high risk of severe respiratory viral diseases, including seasonal influenza, and are five times more likely to be hospitalised with the flu than non-Indigenous people. Here, we showed that the immunogenetic diversity of First Nations peoples of Oceania has the potential to diversify natural killer (NK) cell responses to viral infections and contributes to the increased risk of hospitalization.
Killer cell immunoglobulin-like receptors (KIRs) have an essential role in the control of NK cells, mainly by interacting with polymorphic human leukocyte antigen (HLA) class I molecules.
HLA-A*24:02, which is highly prevalent in Oceania, is associated with poor influenza disease prognosis and is recognised by the highly polymorphic inhibitory NK cell receptor KIR3DL1 (over 200 forms in humans). In this study, we identified an ancient variant of the NK cell receptor KIR3DL1, called KIR3DL1*114, that appears to be exclusive to the people of Oceania. We showed that KIR3DL1*114 has archaic human origin and coevolved with HLA-A*24:02.
KIR3DL1*114+NK cells from First Nations Australian donors are strongly inhibited through binding HLA-A*24:02. A striking feature of the Indigenous KIR3DL1 allotype is its possession of phenylalanine at position 166, instead of a leucine. Structural and binding studies show phenylalanine 166 enhances recognition of HLA-A*24:02, forming multiple unique contacts with HLA-peptide complexes, increasing both affinity and specificity.
This world-first discovery highlights the importance of including diverse populations in genetic studies to better understand disease susceptibility and tailor healthcare approaches when developing disease prevention strategies. For instance, this discovery offers valuable insights into the unique immune responses of First Nations people and could lead to improved strategies for preventing and treating infectious diseases, such as the development of new vaccines and immunotherapies for respiratory illnesses like influenza and COVID-19.