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

2024-10-25

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-A24:02 became the dominant ligand for inhibitory KIR3DL1 in First Nations peoples across Oceania, through positive natural selection. We identify KIR3DL1114, widespread across and unique to Oceania, as an allele lineage derived from archaic humans. KIR3DL1114NK cells from First Nations Australian donors are inhibited through binding HLA-A24:02. The KIR3DL1114 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.

Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia; Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA.

Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.

Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.

Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO 80045, USA.

Department of Structural Biology and Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.

Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO 80045, USA.

Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO 80045, USA.

Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.

Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.

Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.

Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.

Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.

Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO 80045, USA.

Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO 80045, USA; Blood Center of Zhejiang Province, Hangzhou, Zhejiang, China.

Blood Center of Zhejiang Province, Hangzhou, Zhejiang, China.

Stanford Blood Centre, Department of Pathology, Stanford University, Stanford, CA 94305, USA.

Stanford Blood Centre, Department of Pathology, Stanford University, Stanford, CA 94305, USA.

Department of Structural Biology and Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.

Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.

Menzies School of Health Research, Charles Darwin University, Darwin, NT 0810, Australia; Department of Infectious Diseases, Royal Darwin Hospital, Casuarina, NT 0810, Australia.

Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7LF, UK.

Institute of Social and Cultural Anthropology, School of Anthropology and Museum Ethnography, University of Oxford, Oxford OX3 7LF, UK.

Papua New Guinea Institute of Medical Research, Post Office Box 60, Goroka, Papua New Guinea.

Department of Biomolecular Engineering, UC Santa Cruz, Santa Cruz, CA 95064, USA.

Advanced Genomics Unit, Center for Research and Advanced Studies (CINVESTAV), Irapuato 36821, Mexico.

Advanced Genomics Unit, Center for Research and Advanced Studies (CINVESTAV), Irapuato 36821, Mexico.

Jawun Research Centre, Central Queensland University, Cairns, QLD 4870, Australia.

Department of Structural Biology and Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.

Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK. Electronic address: jamie.rossjohn@monash.edu.

Victorian Infectious Diseases Service, The Royal Melbourne Hospital, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC 3000, Australia; Department of Infectious Diseases, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC 3000, Australia. Electronic address: steven.tong@unimelb.edu.au.

Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia. Electronic address: kkedz@unimelb.edu.au.

Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia. Electronic address: agbrooks@unimelb.edu.au.

Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA; Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO 80045, USA; Department of Structural Biology and Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA. Electronic address: paul.norman@cuanschutz.edu.

Cell . 2024 Oct 25:S0092-8674(24)01153-X. doi: 10.1016/j.cell.2024.10.005. Online ahead of print.

1097-4172

https://pubmed.ncbi.nlm.nih.gov/39476840/?otool=iaurydwlib

https://hdl.handle.net/10137/13774

First Nations Australians

HLA

KIR

NK cells

Oceania

immunogenetic diversity

influenza virus

introgression

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

Journal Article

Publication