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.

Keywords: Agent-based modeling; Host-pathogen co-evolution; KIR; NK cell receptors; Viral evasion.

Fig. 1

Cartoon of the NK cell receptor complexes. The NK cell receptor complexes. This figure shows a schematic organization of some of the genes encoded in the NKC (left) and in the KIR region of the LRC (right) for different species. The NKC encodes genes from the CD94 (yellow boxes), NKG2 (blue), and Ly49 (red) families. While higher primates have one copy of a non-functional Ly49 gene (white boxes), lemurs have one functional Ly49, and mice encode 15 Ly49 genes, 11 of which are functional. Lemurs have expanded their CD94/NKG2 system, with three CD94 genes, and eight NKG2 genes. KIRs (orange boxes) are encoded in the LRC. All higher primates share a common organization within this gene complex. Between the four framework genes, i.e. KIR3DL3, KIR2DL4, KIR3DL2, (gray boxes), and the pseudo gene KIR3DP1 (white boxes), the gene content varies across species. Lemurs have only one non-functional copy, and mice do not encode any KIR in the LRC. The gene order was taken from the literature sources mentioned in the text and from Kelley et al. (2005)