Genetics of Natural Killer Cells in Human Health, Disease, and Survival

Abstract

Natural killer (NK) cells have vital functions in human immunity and reproduction. In the innate and adaptive immune responses to infection, particularly by viruses, NK cells respond by secreting inflammatory cytokines and killing infected cells. In reproduction, NK cells are critical for genesis of the placenta, the organ that controls the supply of oxygen and nutrients to the growing fetus. Controlling NK cell functions are interactions of HLA class I with inhibitory NK cell receptors. First evolved was the conserved interaction of HLA-E with CD94:NKG2A; later established were diverse interactions of HLA-A, -B, and -C with killer cell immunoglobulin-like receptors. Characterizing the latter interactions is rapid evolution, which distinguishes human populations and all species of higher primate. Driving this evolution are the different and competing selections imposed by pathogens on NK cell-mediated immunity and by the constraints of human reproduction on NK cell-mediated placentation. Promoting rapid evolution is independent segregation of polymorphic receptors and ligands throughout human populations.

Haplotype-Based Analysis of KIR-Gene Profiles in a South European Population—Distribution of Standard and Variant Haplotypes, and Identification of Novel Recombinant Structures

“…In parallel, the KIR-gene profiles of multiple populations worldwide have been explored in the last two decades, revealing that, whilst many KIR haplotypes and alleles are shared by humans of all ethnicities, notorious differences in their distribution exist, unveiling the evolutionary connections between human groups, and the variable selective pressures exerted on them by the environment (16,40). However, it is noteworthy that many published population studies have not benefited sufficiently from knowledge on KIR polymorphism gained from genomic studies, often reporting only rough analyses of gene content and basic classifications on the "B-ness" or "A-ness" of KIR haplotypes.…”

“…In contrast, "B" haplotypes are distinguished by one or more of the following features: they encode several activating KIR; lack one or more genes for the aforementioned inhibitory KIR; and/or carry KIR2DL5, of uncertain biological role (15). This diversity appears to influence many human health conditions (16).…”

Differential IL-18 Dependence of Canonical and Adaptive NK Cells for Antibody Dependent Responses to P. falciparum

“…These factors may also be important in the context of malaria vaccines, where the choice of adjuvant could influence the cytokine-induced preactivation of canonical NK cell subsets and population differences in the frequencies of adaptive NK cells could impact their role as effectors in the vaccine induced response. The impact of genetic variation-diversity in HLA and killer cell immunoglobulinlike receptors (52)(53)(54) as well as polymorphisms in other NK cell receptors such as CD16 and NKG2C-on the diversity of NK cell responses within and between populations should also be considered.…”

Analysis of Killer Immunoglobulin-Like Receptor Genes in Colorectal Cancer

“…An important element of NK target recognition is the binding of human leucocyte antigen (HLA) class I molecules by killer immunoglobulin-like receptors (KIRs). The KIR gene cluster is located on human chromosome 19, and constitutes a multigene family with genomic diversity with regard to gene content and allelic polymorphism [5] (Figure 1). KIRs have two (2D) or three Ig-like domains (3D), possessing a short (S) or long (L) cytoplasmic tail ( Figure 2).…”

“…Over the last years, KIR genes have been reported strongly associated with disease susceptibility, following a model in which KIRs synergize with HLAs generating genotypes that provide different levels of activation or inhibition [5]. Recognition of HLA by KIR modulates NK function, promoting the attack to cancer cells.…”