The common marmoset monkey (Callithrix jacchus) is a New World primate that is increasingly used in biomedical research as a model organism. Due to the occurrence of natural bone marrow chimerism, it represents a particularly useful primate model in immunological research. In this study, we describe the genomic organization of the CD94, NKG2, and LY49L genes in the NK complex (NKC) of the common marmoset based on complete sequencing of a bacterial artificial chromosome clonal contig. This region of the marmoset NKC is 1.5 times smaller than its human counterpart, but the genes are colinear and orthologous. One exception is the activating NKG2CE gene, which is probably an ancestral form of the NKG2C-and NKG2E-activating receptor genes of humans and great apes. Almost all NK cell receptors are encoded in two gene clusters, the leukocyte receptor complex (LRC) 5 and the NK complex (NKC), which map to human chromosomes 19q13.4 (8) and 12p13 (9), respectively. LRC-encoded receptors contain Ig-like domains, whereas the NKC encodes C-type lectin-like receptors (10). Genes mapping to the NKC include CD94 and the families of Ly49 and NK group (NKG) 2 genes (4, 11). Whereas LY49 and NKG2D molecules form homodimers, CD94 and NKG2 molecules are expressed as heterodimers at the cell surface. The Ly49 gene family is expanded and diverse in rodents (12) and includes activating and inhibitory receptors that are characterized by presence of a positively charged residue in the transmembrane region and ITIM in the cytoplasmic region, respectively (13). The ITIM-containing inhibitory receptor NKG2A and the activating receptor NKG2C form heterodimers with the CD94 molecule, which exhibits neither an activating nor an inhibitory motif. The CD94/NKG2A and the CD94/NKG2C molecules interact with the nonclassical MHC class I ligand HLA-E (14). Recently, binding of CD94 and the activating receptor NKG2E has been demonstrated (15), while the function of NKG2F, which has a truncated extracellular lectin-like domain and binds intracellularly to DAP12, is still unknown (16). Although similarly named, the NKG2D molecule is only distantly related to the other members of the NKG2 family. NKG2D homodimers interact with stress-inducible MHC class I ligands MICA, MICB, ULBP1, ULBP2, ULBP3, and ULBP4 in humans (17-19) and RAET1A, RAET1B, RAET1G, RAET1E, H60, and MULT1 in mice (20,21). NKG2D signaling involves the ITAM-containing adaptor molecules DAP10 and DAP12. Notably, distinct splice products of NKG2D associate with DAP10 and DAP12 in mice (22, 23), but not in humans, where the NKG2D gene is not differentially spliced and its product associates with DAP10 only (24).The CD94 gene is monomorphic and the NKG2 genes are moderately polymorphic in humans and common chimpanzees, and all genes are subject to alternative splicing (25,26). In this study, we show the complete sequence and organization of the CD94-LY49L genomic interval in a New World monkey species, the common marmoset (Callithrix jacchus). The NKC of the common marmoset monkey encodes o...