Genomic view of the origins of cell-mediated immunity.

NKp30 is an activating natural killer cell receptor (NKR) with a single-exon variable (VJ)-type immunoglobulin superfamily (IgSF) domain. Such VJ-IgSF domains predate the emergence of the antigen receptors (immunoglobulin and T cell receptor), which possess the same domain but undergo gene rearrangement. NCR3, the gene encoding NKp30, is present in jawed vertebrates from sharks to mammals; thus, unlike most NKR that are highly divergent among vertebrate taxa, NKp30 is uniquely conserved. We previously hypothesized that an ancestral NCR3 gene was encoded in the proto-major histocompatibility complex (MHC), the region where many immune-related genes have accumulated. Herein, we searched in silico databases to identify NCR3 paralogues and examined their genomic locations. We found a paralogue, NCR3H, in many vertebrates but was lost in mammals. Additionally, we identified a set of voltage-gated sodium channel beta (SCNB) genes as NCR3-distantly-related genes. Like NCR3, both NCR3H and SCNB proteins contain a single VJ-IgSF domain followed by a transmembrane region. These genes map to MHC paralogous regions, originally described in an invertebrate, along with genes encoding cell adhesion molecules involved in NK cell recognition networks. Other genes having no obvious relationship to immunity also map to these paralogous regions. These gene complexes were traced to several invertebrates, suggesting that the foundation of these cellular networks emerged before the genome-wide duplications in early gnathostome history. Here, we propose that this ancestral region was involved in cell-mediated immunity prior to the emergence of adaptive immunity and that NCR3 piggybacked onto this primordial complex, heralding the emergence of vertebrate NK cell/T cells.