Adaptive Admixture of HLA Class I Allotypes Enhanced Genetically Determined Strength of Natural Killer Cells in East Asians.

Zuhu Deng ,Mary Carrington,Ge Sun,Liumei He,Xiaojiang Gao,Peter Parham,Genelle F Harrison,Mingzhong Tang,Siqi Cai,Guobin Zhang,Neda Nemat-Gorgani,Rui Chen,Hong-Yan Zou ,Wen‐Xu Hong ,William H Palmer ,Junjie Zhen ,Lisbeth A Guethlein ,Qi Yu ,Jonathan A Shortt ,Christopher R Gignoux ,Paul J Norman

doi:10.1093/molbev/msab053

Abstract

Human natural killer (NK) cells are essential for controlling infection, cancer, and fetal development. NK cell functions are modulated by interactions between polymorphic inhibitory killer cell immunoglobulin-like receptors (KIR) and polymorphic HLA-A, -B, and -C ligands expressed on tissue cells. All HLA-C alleles encode a KIR ligand and contribute to reproduction and immunity. In contrast, only some HLA-A and -B alleles encode KIR ligands and they focus on immunity. By high-resolution analysis of KIR and HLA-A, -B, and -C genes, we show that the Chinese Southern Han (CHS) are significantly enriched for interactions between inhibitory KIR and HLA-A and -B. This enrichment has had substantial input through population admixture with neighboring populations, who contributed HLA class I haplotypes expressing the KIR ligands B*46:01 and B*58:01, which subsequently rose to high frequency by natural selection. Consequently, over 80% of Southern Han HLA haplotypes encode more than one KIR ligand. Complementing the high number of KIR ligands, the CHS KIR locus combines a high frequency of genes expressing potent inhibitory KIR, with a low frequency of those expressing activating KIR. The Southern Han centromeric KIR region encodes strong, conserved, inhibitory HLA-C-specific receptors, and the telomeric region provides a high number and diversity of inhibitory HLA-A and -B-specific receptors. In all these characteristics, the CHS represent other East Asians, whose NK cell repertoires are thus enhanced in quantity, diversity, and effector strength, likely augmenting resistance to endemic viral infections.

Highlights

Human leukocyte antigen (HLA) class I molecules are critical components of immunity, whose extreme variation associates with resistance and susceptibility to infection, multiple immunemediated diseases and some cancers (Dendrou et al 2018)
HLA-A or -B killer cell immunoglobulin-like receptors (KIR) ligands and those that do not (Guethlein et al 2015). To determine if this pattern is observed in the Chinese Southern Han, we analyzed the HLA-class I genes of healthy individuals
Our analysis shows that the geographic distribution of HLA class I alleles and haplotypes is consistent with human dispersal out of Africa and the distance of their geographical location from Africa

Summary

Introduction

Human leukocyte antigen (HLA) class I molecules are critical components of immunity, whose extreme variation associates with resistance and susceptibility to infection, multiple immunemediated diseases and some cancers (Dendrou et al 2018). KIR are expressed on the surface of NK cells and regulate their functions through binding to HLA class I ligands on other cells (Cooper et al 2009; Long et al 2013) The functions of these interactions are crucial in immunity to aid recognition and elimination of infected or tumorous tissue, and in reproduction to regulate placentation and fetal development (Parham and Moffett 2013). In accordance with these critical and independent roles in human health, KIR and their HLA class I ligands are subject to natural selection, mediating their exceptional diversity across individuals, populations and species (Parham and Moffett 2013; Prugnolle et al 2005). Under-explored are the scale and characteristics of KIR and HLA class I combinatorial diversity worldwide, and the processes that shape this diversity

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