The Journal of Experimental Medicine
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Published online 13 March 2006 doi:10.1084/jem.20051884
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 3, 633-645
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ARTICLE

 Roles for HLA and KIR polymorphisms in natural killer cell repertoire selection and modulation of effector function

Makoto Yawata1, Nobuyo Yawata1, Monia Draghi1, Ann-Margaret Little2,3, Fotini Partheniou2, and Peter Parham1

1 Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305
2 Histocompatibility Laboratories, The Anthony Nolan Trust and 3 Department of Haematology, The Royal Free Hospital, London, NW3 2QG, England, UK

CORRESPONDENCE Peter Parham: peropa{at}stanford.edu OR Makoto Yawata: myawata{at}stanford.edu

Interactions between killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands regulate the development and response of human natural killer (NK) cells. Natural selection drove an allele-level group A KIR haplotype and the HLA-C1 ligand to unusually high frequency in the Japanese, who provide a particularly informative population for investigating the mechanisms by which KIR and HLA polymorphism influence NK cell repertoire and function. HLA class I ligands increase the frequencies of NK cells expressing cognate KIR, an effect modified by gene dose, KIR polymorphism, and the presence of other cognate ligand–receptor pairs. The five common Japanese KIR3DLI allotypes have distinguishable inhibitory capacity, frequency of cellular expression, and level of cell surface expression as measured by antibody binding. Although KIR haplotypes encoding 3DL1*001 or 3DL1*005, the strongest inhibitors, have no activating KIR, the dominant haplotype encodes a moderate inhibitor, 3DL1*01502, plus functional forms of the activating receptors 2DL4 and 2DS4. In the population, certain combinations of KIR and HLA class I ligand are overrepresented or underrepresented in women, but not men, and thus influence female fitness and survival. These findings show how KIR–HLA interactions shape the genetic and phenotypic KIR repertoires for both individual humans and the population.

Abbreviations used: KIR, killer cell immunoglobulin-like receptor; LD, linkage disequilibrium; mfi, mean fluorescence intensity.

M. Yawata and N. Yawata contributed equally to this work.


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