LITMAN, G.W.: Novel Immune-Type Receptor Genes and the Origins of Adaptive and Innate Immune Recognition

Prototypic forms of novel immune-type receptors (NITRs) encode a variable (V) region, a unique V/C2 domain, a transmembrane region and a cytoplasmic tail containing immunoreceptor tyrosine-based inhibition motifs (ITIMs). NITRs exhibit properties of adaptive and innate immune receptors that encode diversified V regions but do not undergo somatic rearrangement. Studies of NITRs in three different bony fish model systems have identified a number of different forms, each of which encodes an N-terminal V region but otherwise varies in the: number of extracellular immunoglobulin domains, number and location of joining (J) region-like motifs, presence of transmembrane regions, presence of charged residues within transmembrane regions, presence of cytoplasmic tails, and/or distribution of ITIM(s) within the cytoplasmic tails. V region-containing NITRs constitute a far more complex family than recognized originally and include individual members that potentially function through inhibitory as well as activatory mechanisms. Comparison of the predicted structures of the NITRs have identified several regions of identity. A novel cloning strategy has been devised that selects for secretory and transmembrane proteins that encode the shared motifs found in NITRs. Using this approach, related genes have been identified in protochordates and early representative jawed vertebrates. As regards the latter, NITR-like genes have been identified in cartilaginous fish, whereas related but structurally distinct multigene families have been identified in protochordates. Taken together, these studies indicate that leukocyte regulatory receptors, such as those mediating natural killer function, emerged early in vertebrate evolution. In addition, newly discovered genes in protochordates may represent significant links between innate and adaptive immunity.