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

Abstract

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.

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

“…From this, testable hypotheses can be formed about the extent to which each gene or allele, in conjunction with ligand variation, can predispose to a phenotype. For example, the cell surface expression of KIR3DL1 and the ability to recognize HLA‐Bw4 ligand vary according to allele, and hence KIR3DL1 alleles should be analysed accordingly in the disease context 25, 38, 58, 72. Similarly, polymorphism in the extracellular domain of KIR2DL1 influences the binding affinity to HLA‐C2 34, 40.…”

“…KIR3DL1*004 null allele is present at a mean frequency of 24·2% (SD 10·3) in worldwide populations 56. The frequency of cells positive for a given KIR is tightly linked to KIR gene copy number; a donor with two copies of KIR3DL1 will have a greater frequency of KIR3DL1 + NK cells than donors with only one copy,37, 38, 142 suggesting that each KIR gene copy is regulated independently. Additionally, NK cell KIR expression is related to cellular differentiation.…”

Receptor systems controlling natural killer cell function are genetically stratified in Europe

“…10,12,13 3DL1-mediated NK cell inhibition through Bw4 is considered a strong inhibitory interaction. 14 A number of activatory KIR (2DS1, 2DS2) also bind to HLA class I, albeit with weaker affinity and variation in the presence or absence of each can influence NK cell function. 15,16 Several studies indicate that KIRs have evolved in humans to fulfill diverse functions as a consequence of a wide range of evolutionary pressures.…”

“…The opposing functions of activatory and inhibitory KIR is believed to reflect underlying processes of balancing and positive selection in response to pressures imposed by pathogens and coevolution with their rapidly evolving HLA class I ligands. 14,[17][18][19][20] Evidence also suggests the emergence of KIR to fulfill important roles during pregnancy [21][22][23] in which it has been shown that they influence the role of uterine NK cell in vascular remodeling during fetal trophoblast cell invasion of the deciduas. 24 As a likely consequence of these selective pressures, KIR diversity at the genetic, phenotypic and functional levels is immense.…”

Associations of killer cell immunoglobulin-like receptor genes with complications of rheumatoid arthritis

“…29 The 2DS4del form prevails in KIR2DS4-positive Caucasians, 30,31 whereas the opposite is true for Oriental populations. 28,32 Yen et al 24 did not differentiate between 2DS4fl and 2DS4del alleles, so the nature of their RA-associated KIR2DS4 molecule (cell membrane-activating receptor vs soluble 2DS4del protein, possibly masking a ligand for 2DS4fl and other receptors) is not known. It therefore seems premature to speculate on the role of KIR2DS4 in the Taiwanese' susceptibility to RA.…”