The identification of MHC class I ligands for rhesus macaque KIRs is fundamental to Rabbit Polyclonal to FOXD3. our basic understanding of KIR and MHC class I co-evolution and to the study of NK cell responses in this nonhuman primate model for AIDS and other viral diseases. for Mamu-KIR3DL01 recognition since substitutions in this region abrogated Mamu-KIR3DL01+ NK cell inhibition. However the presence of a Bw4 motif was not sufficient for recognition since another Bw4 molecule Mamu-B*017:01 failed to suppress the cytolytic activity of these NK cells. Replacement of three residues in Mamu-B*017:01 predicted to be KIR-contacts based on the 3-dimensional structure of the human KIR3DL1-HLA-Bw4 complex with the corresponding residues at these positions for the other Mamu-Bw4 ligands restored Mamu-KIR3DL01+ NK cell inhibition. These results define the ligand specificity of one of the most polymorphic and commonly expressed KIRs in the rhesus macaque and reveal similarities in Bw4 recognition by Mamu-KIR3DL01 and human KIR3DL1 despite the absence of an orthologous relationship between these two KIRs or conservation of surface residues predicted to interact with MHC class I ligands. Introduction NK cells are able to recognize and kill virus-infected cells and tumor cells without prior antigenic stimulation and therefore constitute an important innate cellular defense against infectious diseases and cancers. NK cell responses in primates are regulated in part through interactions between two highly polymorphic molecules the killer-cell Ig-like receptors (KIRs) on NK cells and their MHC class I ligands on target cells. Depending on sequences in their transmembrane and cytoplasmic domains KIRs can transduce either Cor-nuside inhibitory or activating signals. In the case of inhibitory KIRs NK cell activation is usually suppressed upon receptor engagement of MHC class I ligands on the surface of healthy cells. Thus NK cells bearing inhibitory KIR may become activated upon disruption of ligand recognition either as a consequence of MHC class I downregulation due to viral contamination (1-5) deletion of genes during tumor progression (6) or MHC class I presentation of antagonistic peptides (7). Genetic evidence suggests that and polymorphisms play a significant role in determining the course of infection for several human pathogens including hepatitis C computer virus (8) hepatitis B computer virus (9 10 human papilloma computer virus (11 12 HSV (13) and HIV (14 15 However studies addressing the functional implications of these observations have been limited by the lack of a suitable animal model. Mice and other rodents do not express KIRs but instead use C-type lectin-like molecules encoded by the genes as polymorphic NK cell receptors for MHC class I ligands (16). Moreover KIRs appear to be evolving at a particularly rapid pace in primates (17-20). As a consequence there is little conservation among the genes of different species Cor-nuside and it is not possible to predict the specificity of KIR-MHC class I interactions on Cor-nuside the basis of sequence comparisons with human KIRs. The rhesus macaque is an important animal model for AIDS research (21) and for other viral diseases caused by Epstein-Barr computer virus (22) cytomegalovirus (23) and Kaposi’s sarcoma-associated herpesvirus (24). Immunogenetic characterization of this species has also contributed to our basic understanding of the co-evolution of and genes. Rhesus macaques have duplicated (and -genes which match and -in human beings (25 26 Nonetheless they don’t have a locus since represents a duplication of the ancestral gene that happened following the divergence of apes and Aged Globe monkeys (25 26 You can find as much as four genes and an undefined and adjustable amount of genes on any provided haplotype within the rhesus macaque (27 28 Relative to and co-evolution macaques absence lineage III genes which encode KIR2DL/S particular for HLA-C (29 30 and rather have an extended repertoire of genes seen as a intensive polymorphism (20 29 Certainly 19 specific genes have already been determined in rhesus macaques (31 33 The reputation of MHC course I substances by Cor-nuside individual KIRs is mainly dependant on sequences within the ligand α1 and α2 domains. All HLA-B substances plus some HLA-A substances can be categorized as either Bw4 or Bw6 allotypes based on residues at positions 77-83 within the α1 area (34). KIR3DL1 may be the many polymorphic individual KIR and identifies diverse HLA course I ligands that talk about a Bw4 theme (35). The contribution of Bw4 residues to ligand reputation by KIR3DL1 was lately corroborated by way of a crystal framework of KIR3DL1*001 in complicated with HLA-B*5701 which uncovered multiple contacts between your D1 area of KIR3DL1*001 and Bw4.