Abstract

Interactions of killer cell immunoglobulin-like receptors (KIRs) with major histocompatibility complex (MHC) class I ligands diversify natural killer cell responses to infection. By analyzing sequence variation in diverse human populations, we show that the KIR3DL1/S1 locus encodes two lineages of polymorphic inhibitory KIR3DL1 allotypes that recognize Bw4 epitopes of protein">HLA-A and HLA-B and one lineage of conserved activating KIR3DS1 allotypes, also implicated in Bw4 recognition. Balancing selection has maintained these three lineages for over 3 million years. Variation was selected at D1 and D2 domain residues that contact HLA class I and at two sites on D0, the domain that enhances the binding of KIR3D to HLA class I. HLA-B variants that gained Bw4 through interallelic microconversion are also products of selection. A worldwide comparison uncovers unusual KIR3DL1/S1 evolution in modern sub-Saharan Africans. Balancing selection is weak and confined to D0, KIR3DS1 is rare and KIR3DL1 allotypes with similar binding sites predominate. Natural killer cells express the dominant KIR3DL1 at a high frequency and with high surface density, providing strong responses to cells perturbed in Bw4 expression.

1. Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
2. Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
3. Stanford Genome Technology Center, Stanford University School of Medicine, California Avenue, Palo Alto, California 94304, USA.
4. Department of Preclinical Sciences, Faculty of Medical Sciences, University of West Indies, St. Augustine, Trinidad and Tobago.
5. Department of Transfusion Medicine, Faculty of Medicine and Siriraj Hospital, Mahidol University, Bangkok, Thailand.
6. School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 402, Taiwan.
7. Immunology Service, Hospital Universitari Son Dureta, 07014 Palma, Spain.
8. Istanbul Medical Faculty, Department of Physiology, Istanbul University, Turkey.
9. CBR Institute for Biomedical Research, Boston, Massachusetts 02115, USA.
10. Department of Medicine, Aga Khan University Hospital, Karachi, Pakistan.
11. Department of Clinical Immunology, REA Centre, 0160 Tbilisi, Republic of Georgia.
12. Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana.
13. Centre of Experimental Medicine Miguel Layrisse, Venezuelan Research Institute (IVIC), 21827 Caracas, Venezuela.
14. Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea.
15. Centre for Advanced Studies in Functional Genomics, School of Biological Sciences, Madurai Kamaraj University, Madurai 625-021 India.
16. Hungkuang Institute of Technology, Hungkuang University, Taichung 433, Taiwan.
17. Centre for Nephrology and The Anthony Nolan Trust, Royal Free and University College Medical School, London NW3 2QG, UK.
18. Moorfields Eye Hospital, 162 City Road, London EC1V 2PD, UK.
19. Clinical Transplantation Laboratory, Guy's and St. Thomas' Foundation Trust and King's College, London SE1 9RT, UK.
20. Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.

Correspondence to: Paul J Norman¹ e-mail: paul.norman@stanford.edu

Correspondence to: Peter Parham¹ e-mail: peropa@stanford.edu.

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