Primate‐specific regulation of natural killer cells

Abstract

SummaryNatural killer (NK) cells are circulating lymphocytes that function in innate immunity and placental reproduction. Regulating both development and function of NK cells is an array of variable and conserved receptors that interact with major histocompatibility complex (MHC) class I molecules. Families of lectin-like and immunoglobulin-like receptors are determined by genes in the natural killer (NKC) and leukocyte receptor (LRC) complexes, respectively. As a consequence of the strong, varying pressures on the immune and reproductive systems, NK cell receptors and their MHC class I ligands evolve rapidly, are highly diverse, and exhibit dramatic species-specific differences. The variable, polymorphic family of killer cell immunoglobulin-like receptors (KIR) that regulate human NK cell development and function evolved recently, from a single-copy gene during the evolution of simian primates. Our studies of KIR and MHC class I genes in representative species show how these two unlinked but functionally intertwined genetic complexes have co-evolved. In humans, combinations of KIR and HLA class I factors are associated with infectious diseases, including HIV/AIDS, autoimmunity, reproductive success and the outcome of therapeutic transplantation. The extraordinary, and unanticipated, divergence of human NK cell receptors and MHC class I ligands from their mouse counterparts can in part explain the difficulties experienced in finding informative mouse models for human diseases. Non-human primate models have far greater potential, but to realize their promise will first require more complete definition of the genetics and function of KIR and MHC variation in non-human primate species, at a level comparable to that achieved for the human species. KeywordsNon-human primates; NK cells; KIR; MHC; innate immunity Natural killer (NK) cells comprise 5-25% of the lymphocytes circulating in human peripheral blood [1,2]. NK cells are larger than circulating B and T lymphocytes, having a well-developed cytoplasm that contains cytotoxic granules. NK cells were described by morphologists as large granular lymphocytes long before their immunological properties became a subject for study in the 1970s [3][4][5][6]. At that time numerous immunologists were studying antigen specificity and major histocompatibility complex (MHC) restriction of the cytotoxic T cells that arose from long-term stimulation with antigen and cytokines in culture. The defining property that distinguished NK cells from killer T cells was their propensity to kill certain tumor cell lines, such as the K562 erythroleukemia cell line, without needing an extensive period of in vitro stimulation and proliferation. NK cells were thus seen to have a natural or inherent ability to kill damaged or dangerous cells. They are also potent secretors of cytokines, notably interferon-γ. The kinetics observed in culture reflect those of the immune response to infection: NK cells are fast-acting lymphocytes that NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ...

Synergistic inhibition of natural killer cells by the nonsignaling molecule CD94

“…Inhibitory interactions are mediated by receptors for self-MHC class I. Most species have at least two discrete gene families of inhibitory receptors for MHC class I: the CD94-NKG2A C-type lectin-like receptor system and either the related Ly49 family of receptors or the unrelated killer cell Ig-like receptors (KIR) (2). The KIR family is important in humans and other primates, having undergone extensive diversification under positive selection.…”

Identification of the Nephropathy-Susceptibility Locus HIVAN4

“…Although these intervals are large, the availability of multiple crosses now enables significant refinement of positional candidates by comparison of haplotypes among inbred strains. 21 Thus, there are several noteworthy genes among the refined list of candidates at the HIVAN4 locus: a cluster of natural killer cell lectin-like receptor genes, which encode proteins important for defense against pathogens, [22][23][24][25][26] and several genes (Bid, A2m, Cd69, Grin2b, Pik3c2g, Plcz1, Itpr2) with potential interaction with HIV-1. Of note, variation in Klra8 gene, encoding a receptor important for natural killer cell cytoxicity, is associated with differential susceptibility to CMV infection in the mouse but is unlikely to be causal for HIVAN because FVB and BALB have a susceptibility haplotype to CMV infection 23 Another positional candidate, Ptpro, encodes a podocyte expressed protein and has dysregualed expression in HIVAN 27,28 but did not demonstrate a cis-eQTL on additional analysis.…”

NK cell receptors: evolution and diversity

“…Nevertheless, in the orangutan and man's more closely related ancestors Figure 1 (the gorilla, the common chimpanzee and the pygmy chimpanzee) lineage III KIR have expanded, implying that MHC and the KIR are co-evolving (Abi-Rached et al, 2010b). Similarly in the old world monkeys the expansion of MHC-A/B locus has led to expansion of lineage II KIR, and in the hoolock gibbon loss of MHC-G corresponds to loss of the lineage I gene KIR2DL4, which has been shown to be relatively conserved amongst higher primates (Abi-Rached et al, 2010a;Parham et al, 2010). Whilst humans and chimpanzees share MHC-A, -B and -C loci, they share relatively few KIR genes.…”