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Publication Abstract from PubMed

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.

An archaic HLA class I receptor allele diversifies natural killer cell-driven immunity in First Nations peoples of Oceania.,Loh L, Saunders PM, Faoro C, Font-Porterias N, Nemat-Gorgani N, Harrison GF, Sadeeq S, Hensen L, Wong SC, Widjaja J, Clemens EB, Zhu S, Kichula KM, Tao S, Zhu F, Montero-Martin G, Fernandez-Vina M, Guethlein LA, Vivian JP, Davies J, Mentzer AJ, Oppenheimer SJ, Pomat W, Ioannidis AG, Barberena-Jonas C, Moreno-Estrada A, Miller A, Parham P, Rossjohn J, Tong SYC, Kedzierska K, Brooks AG, Norman PJ Cell. 2024 Nov 27;187(24):7008-7024.e19. doi: 10.1016/j.cell.2024.10.005. Epub , 2024 Oct 29. PMID:39476840^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.