The genetic and evolutionary balances in human NK cell receptor diversity

Abstract

In primates and cattle two ancient killer-cell immunoglobulin-like receptor (KIR) lineages independently evolved to become diverse NK cell receptors. In mice, KIR genes were sidelined to the X chromosome, a possible consequence of pathogen-mediated selection on the receptor for IgA-Fc. In humans, KIR uniquely form two omnipresent haplotype groups (A and B), postulated here to play complementary and necessary roles in immune defense and reproduction. The basis of KIR3DL1/S1 polymorphism is three ancient lineages maintained by long-term balancing selection and present in all human populations. Conserved and variable NK cell receptors produce structurally diverse NK cell receptor repertoires within a defined range of missing-self-response.

Introduction

Natural killer (NK) cells are a heterogeneous population of circulating lymphocytes that contribute to the immune response against infection and also to the biology of mammalian reproduction. As was formerly established for CD8 T cells, the interactions of MHC class I molecules with specific lymphocyte receptors are proving to be major mechanisms that influence both the developmental maturation of NK cells and the execution of their effector functions. Comparative studies, of individuals, population and species have shown that some of the interactions between MHC class I and NK cell receptors have been highly conserved while others are diverse and rapidly evolving under natural selection for better defence and reproduction. NK cells achieve diversity through germ-line mutation, contrasting with the somatic mutation used by the T-cell receptors. In this review, which is in part based upon research seminars I gave at Cambridge University during a sabbatical with John Trowsdale and Ashley Moffett in the autumn of 2006, I will consider five topics that have emerged from our studies to understand the structure, function and evolution of NK cell receptors for MHC class I.

The first topic concerns the convergent evolution of structurally different proteins as highly variable NK cell receptors for classical MHC class I molecules. Why do horses follow mice in their use of Ly49 receptors, while the cattle have taken the human option: the killer-cell immunoglobulin-like receptors (KIR). The second topic concerns the compact organization of the human leukocyte receptor complex (LRC), which contains genes for the KIR and many factors involved in defense and reproduction. Because of linkage and linkage disequilibrium, the selection on one locus can affect the others. In particular, can selection on the gene encoding the Fc receptor for monomeric IgA explain the lack of KIR genes in the LRC of the mouse? The third topic considers the different and potentially conflicting demands of defense and reproduction, and the necessity of both for the survival of mammalian populations and species. Evidence is presented that suggests the model in which the group A KIR haplotypes are more adapted to immune defense and the group B KIR haplotypes are more adapted to reproduction. As far as is known all human populations maintain a balance between the A and B KIR haplotypes, and the same is true for the three allelic lineages of the highly polymorphic KIR3DL1/S1 locus, the fourth topic discussed. At this locus the most common allele is arguably the one we know least about what it does. In the final topic I discuss recent studies to examine the heterogeneity of human NK cells and how it is influenced by the extraordinary allotypic variation of HLA class I and the KIRs. What can be said about the rules that govern and restrain populations of NK cells.