Killer Inhibitory Receptor Composition

Killer cell immunoglobulin-like receptors (KIRs) are immune receptors expressed on cells of the innate immune system (NK cells and certain T-cells). KIR genes form a rapidly evolving and diverse gene family. KIRs recognize MHC molecules on cells of self and can inhibit natural killer cell activation. KIRs contribute to an important innate immune monitoring of steady intracellular sampling and declaration of cell content on cell surfaces by MHC molecules. Some KIRs have an activating function on killer cells and probably evolved secondarily from inhibitory KIRs, possibly in response to pathogens that produce MHC-mimicking molecules. Humans have 15 different KIR genes encoding receptors specific for the polymorphic determinants of MHC class I molecules (HLA-A, B and C). Chimpanzees have fixed Patr-A, B, and C genes that are orthologous (identical by descent) to human HLA-A, B, C. In contrast most chimpanzee KIR genes are not orthologous to human genes. Humans, chimpanzees, bonobos, gorillas, and orangutans share four derived lineages of KIR genes, which evolved from an ancestral KIR ~ 135 million years ago. Within these lineages, each species has independently evolved different numbers of KIRs with either inhibiting or activating function. For example, humans only possess seven lineage III KIR genes and chimpanzees have nine. Of these, only two are orthologous, all others evolved differently in these two species after they separated from their last common ancestor. Humans have more activating KIR than inhibitory ones, whereas chimpanzees have twice as many inhibitory than activating KIRs. Bonobos appear to have relatively fewer KIR genes than humans or chimpanzees. In humans, different haplotypes vary with respect to the number of active KIR genes they carry and there are important differences in haplotype frequencies between regional populations (somewhat mirroring MHC haplotype variation). Human ancestors’ capacity to populate new and more varied habitats combined with past population bottlenecks may have uniquely fashioned the composition of human KIRs and their functions.