An archaic HLA class I receptor allele diversifies natural killer cell-driven immunity in First Nations peoples of Oceania
Authors:
- Loh, Liyen
- Saunders, Philippa M.
- Faoro, Camilla
- Font-Porterias, Neus
- Nemat-Gorgani, Neda
- Harrison, Genelle F.
- Sadeeq, Suraju
- Hensen, Luca
- Wong, Shu Cheng
- Widjaja, Jacqueline
- Clemens, E. Bridie
- Zhu, Shiying
- Kichula, Katherine M.
- Tao, Sudan
- Zhu, Faming
- Montero-Martin, Gonzalo
- Fernandez-Vina, Marcelo
- Guethlein, Lisbeth A.
- Vivian, Julian P.
- Davies, Jane
- Mentzer, Alexander J.
- Oppenheimer, Stephen J.
- Pomat, William
- Ioannidis, Alexander G.
- Barberena-Jonas, Carmina
- Moreno-Estrada, Andrés
- Miller, Adrian
- Parham, Peter
- Rossjohn, Jamie
- Tong, Steven Y.C.
- Kedzierska, Katherine
- Brooks, Andrew G.
- Norman, Paul J.
Details:
Cell, Volume 187, Issue 24, 2024-11-27
Article Link: Click here
Genetic variation in host immunity impacts the disproportionate burden of infectious diseases that can be experienced by First Nations peoples. Polymorphic human leukocyte antigen (HLA) class I and killer cell immunoglobulin-like receptors (KIRs) are key regulators of natural killer (NK) cells, which mediate early infection control. How this variation impacts their responses across populations is unclear. We show that HLA-A∗24:02 became the dominant ligand for inhibitory KIR3DL1 in First Nations peoples across Oceania, through positive natural selection. We identify KIR3DL1∗114, widespread across and unique to Oceania, as an allele lineage derived from archaic humans. KIR3DL1∗114+NK cells from First Nations Australian donors are inhibited through binding HLA-A∗24:02. The KIR3DL1∗114 lineage is defined by phenylalanine at residue 166. Structural and binding studies show phenylalanine 166 forms multiple unique contacts with HLA-peptide complexes, increasing both affinity and specificity. Accordingly, assessing immunogenetic variation and the functional implications for immunity are fundamental toward understanding population-based disease associations.