The evolution of natural killer cell receptors

Abstract

Natural killer (NK) cells are immune cells that play a crucial role against viral infections and tumors. To be tolerant against healthy tissue and simultaneously attack infected cells, the activity of NK cells is tightly regulated by a sophisticated array of germline-encoded activating and inhibiting receptors. The best characterized mechanism of NK cell activation is “missing self” detection, i.e., the recognition of virally infected or transformed cells that reduce their MHC expression to evade cytotoxic T cells. To monitor the expression of MHC-I on target cells, NK cells have monomorphic inhibitory receptors which interact with conserved MHC molecules. However, there are other NK cell receptors (NKRs) encoded by gene families showing a remarkable genetic diversity. Thus, NKR haplotypes contain several genes encoding for receptors with activating and inhibiting signaling, and that vary in gene content and allelic polymorphism. But if missing-self detection can be achieved by a monomorphic NKR system why have these polygenic and polymorphic receptors evolved? Here, we review the expansion of NKR receptor families in different mammal species, and we discuss several hypotheses that possibly underlie the diversification of the NK cell receptor complex, including the evolution of viral decoys, peptide sensitivity, and selective MHC-downregulation.

Short tandem repeats, segmental duplications, gene deletion, and genomic instability in a rapidly diversified immune gene family

“…This is evident from the KIR gene family, which is tightly clustered and shows variations in gene copy numbers for different human haplotypes in addition to sequence diversity in the population based on 15 to 112 alleles for different loci [9]. Variations in the KIR region is thought to result from genomic instability driven by shared sequences within and surrounding the genes, including minisatellite sequences in the first intron, all of which can lead to crossing over among the tandemly arranged genes, expansion and contraction of gene numbers from meiotic mispairing, in addition to recombination, gene conversion, domain shuffling, duplications and deletions and single nucleotide polymorphisms ([45, 46], reviewed in [47, 48]). Similar to the assembly problems for the Sp185/333 gene family, the attributes of the KIR family have also resulted in very poor assembly in macaque genome sequences [49].…”

Adaptive Memory of Human NK-like CD8+ T-Cells to Aging, and Viral and Tumor Antigens

“…In addition to CD8 + T lymphocytes, natural killer (NK) cells have a crucial role in the recognition and killing of virus-infected/tumor cells, but unlike CD8 + T-cells, they use a repertoire of germ-line encoded inhibitory/activating receptors that recognize “missing self”/“altered-self” antigens on the target cells leading to cytotoxicity and cytokine production (3). These NK cell receptors (NKRs) are also expressed on certain subsets of T-cells.…”

Interferon-Dependent Induction of Clr-b during Mouse Cytomegalovirus Infection Protects Bystander Cells from Natural Killer Cells via NKR-P1B-Mediated Inhibition

“…Previous studies have shown that infection of various mouse and rat cells with a number of viruses (MCMV, RC-MV-E, vaccinia, ectromelia) promotes a rapid loss of mouse Clr-b ( Clec2d ) and the rat Clr-b homolog rClr-11 ( Clec2d11 ) at both the steady-state transcript and cell surface levels [6,16,18,19] . To distinguish between infected and uninfected (bystander) cells at the single cell level, we infected mouse NIH3T3 fibroblasts over an early time course using a modified MCMV-GFP reporter virus in which an enhanced GFP transgene is driven by an immediate early gene (ie1/3) promoter in the MCMV-Smith (VR-194) strain [19][20][21] .…”

“…All of these receptors are encoded within the NK gene complex (NKC) located on mouse chromosome 6, rat chromosome 4, and human chromosome 12 [5] , yet a number of loci encoding other NKR, including NKp46 ( Ncr1 ) and 2B4 ( Cd244 ), are located outside the NKC [reviewed in 6 ].…”