Loss and Gain of Natural Killer Cell Receptor Function in an African Hunter-Gatherer Population

Abstract

Modulating natural killer cell functions in human immunity and reproduction are diverse interactions between the killer cell immunoglobulin-like receptors (KIR) of Natural Killer (NK) cells and HLA class I ligands on the surface of tissue cells. Dominant interactions are between KIR2DL1 and the C2 epitope of HLA-C and between KIR2DL2/3 and the C1 epitope of HLA-C. KhoeSan hunter-gatherers of Southern Africa represent the earliest population divergence known and are the most genetically diverse indigenous people, qualities reflected in their KIR and HLA genes. Of the ten KhoeSan KIR2DL1 alleles, KIR2DL1*022 and KIR2DL1*026 likely originated in the KhoeSan, and later were transmitted at low frequency to the neighboring Zulus through gene flow. These alleles arose by point mutation from other KhoeSan KIR2DL1 alleles that are more widespread globally. Mutation of KIR2DL1*001 gave rise to KIR2DL1*022, causing loss of C2 recognition and gain of C1 recognition. This makes KIR2DL1*022 a more avid and specific C1 receptor than any KIR2DL2/3 allotype. Mutation of KIR2DL1*012 gave rise to KIR2DL1*026, causing premature termination of translation at the end of the transmembrane domain. This makes KIR2DL1*026 a membrane-associated receptor that lacks both a cytoplasmic tail and signaling function. At higher frequencies than their parental allotypes, the combined effect of the KhoeSan-specific KIR2DL1*022 and KIR2DL1*026 is to reduce the frequency of strong inhibitory C2 receptors and increase the frequency of strong inhibitory C1 receptors. Because interaction of KIR2DL1 with C2 is associated with risk of pregnancy disorder, these functional changes are potentially advantageous. Whereas all other KhoeSan KIR2DL1 alleles are present on a wide diversity of centromeric KIR haplotypes, KIR2DL1*026 is present on a single KIR haplotype and KIR2DL1*022 is present on two very similar haplotypes. The high linkage disequilibrium across their haplotypes is consistent with a recent emergence for these KIR2DL1 alleles that have distinctive functions.

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

“…By comparison, the KhoeSan population from Southern Africa has one of the highest aggregate frequencies of HLA‐C allotypes expressing the C2 motif. Here, a KIR allotype that switched binding specificity entirely from C2 to C1 has evolved 34. Both of these binding changes are due to substitutions at residues subject to balancing selection (Fig.…”

“…3). Even a single nucleotide mutation can dramatically change receptor expression,25, 31, 32, 33 ligand specificity34, 35, 36 or signalling strength. KIR gene copy number variation influences NK cell education, shaping the NK cell repertoire 37.…”

“…Multiple novel KIR alleles may be discovered during population studies, and molecular analysis identifies the most functionally important. An example is KIR 2 DL 1*022 , which was discovered in the southern African KhoeSan population (a) and which differs from its parental allele KIR 2 DL 1*001 by a single nucleotide substitution in codon 44 (b) 34. Phylogenetic analyses that included the most closely related KIR from other hominoid species identified that residue 44 has been subject to balancing selection (c) 66.…”

“…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. Over 200 associations of KIR genes with disease resistance or susceptibility are published,56, 73 and the handful studied at high resolution are proving informative 58, 74, 75, 76.…”

“…Other residues are involved in the interaction however, and their polymorphism means that there is a range of binding characteristics determined by KIR allotype. The interactions of KIR2DL are further diversified by polymorphism within the subsets of C1‐bearing and C2‐bearing HLA allotypes 34, 103. The basis for these hierarchies may occur due to polymorphism at sites other than position 80, or the distinct repertoires of peptide presented by the different HLA‐C allotypes 106.…”