Abstract
Natural killer (NK) cells serve essential functions in immunity and reproduction. Diversifying these functions within individuals and populations are rapidly-evolving interactions between highly polymorphic major histocompatibility complex (MHC) class I ligands and variable NK cell receptors. Specific to simian primates is the family of Killer cell Immunoglobulin-like Receptors (KIR), which recognize MHC class I and associate with a range of human diseases. Because KIR have considerable species-specificity and are lacking from common animal models, we performed extensive comparison of the systems of KIR and MHC class I interaction in humans and chimpanzees. Although of similar complexity, they differ in genomic organization, gene content, and diversification mechanisms, mainly because of human-specific specialization in the KIR that recognizes the C1 and C2 epitopes of MHC-B and -C. Humans uniquely focused KIR recognition on MHC-C, while losing C1-bearing MHC-B. Reversing this trend, C1-bearing HLA-B46 was recently driven to unprecedented high frequency in Southeast Asia. Chimpanzees have a variety of ancient, avid, and predominantly inhibitory receptors, whereas human receptors are fewer, recently evolved, and combine avid inhibitory receptors with attenuated activating receptors. These differences accompany human-specific evolution of the A and B haplotypes that are under balancing selection and differentially function in defense and reproduction. Our study shows how the qualitative differences that distinguish the human and chimpanzee systems of KIR and MHC class I predominantly derive from adaptations on the human line in response to selective pressures placed on human NK cells by the competing needs of defense and reproduction.
Highlights
Natural killer (NK) cells are lymphocytes that contribute to both the immune and reproductive systems
Controlling both NK cell development and effector function is a variety of interactions between NK cell receptors and their ligands [6], the class I molecules of the major histocompatibility complex (MHC): called the HLA complex in humans
Essential to NK cell development, diversification and function are variable families of surface receptors that recognize variable determinants of polymorphic major histocompatibility complex (MHC) class I molecules, better known as the tissue types matched in clinical organ transplantation
Summary
Natural killer (NK) cells are lymphocytes that contribute to both the immune and reproductive systems. During embryo implantation and placentation, NK cells control the trophoblastmediated widening of maternal blood vessels necessary to nourish the fetus throughout pregnancy [5]. Controlling both NK cell development and effector function is a variety of interactions between NK cell receptors and their ligands [6], the class I molecules of the major histocompatibility complex (MHC): called the HLA complex in humans. Pointing to the clinical importance of these interactions, various combinations of HLA and KIR factors associate with the outcome of viral infection, susceptibility to autoimmune disease, relapse of leukemia following therapeutic transplantation, and reproductive success [9,10,11]
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