An archaic HLA class I receptor allele diversifies natural killer cell-driven immunity in First Nations peoples of Oceania

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 ORCID: https://orcid.org/0000-0002-2020-7522, Tong, Steven Y.C., Kedzierska, Katherine, Brooks, Andrew G. and Norman, Paul J. 2024. An archaic HLA class I receptor allele diversifies natural killer cell-driven immunity in First Nations peoples of Oceania. Cell 187 (24) , pp. 7008-7024. 10.1016/j.cell.2024.10.005

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Elsevier
ISSN:	0092-8674
Date of First Compliant Deposit:	15 November 2024
Date of Acceptance:	3 October 2024
Last Modified:	15 Jan 2025 11:02
URI:	https://orca.cardiff.ac.uk/id/eprint/174029

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