Interests in Dr. Litman's laboratory are centered on the genetics and function of diversified innate immune receptors and alternative mediators of adaptive immunity. The novel immune-type receptors (NITRs), which were identified originally in pufferfish, a compact genome model system, as well as in zebrafish, an important developmental model system, represent one such multigene family. In terms of both their polymorphic and polygenic characters, NITRs possess diversified immunoglobulin-type variable (V) regions but otherwise resemble the activating/inhibitory killer cell immunoglobulin-type receptors (KIRs), which effect natural killer function in man. Present studies are focused on characterizing the genetic diversity in NITRs as well as their ligand binding specificities; an NITR expressed by an NK cell line exhibits highly specific reactivity for a determinant on allogeneic target cells. The functional relationship of NITRs to KIRs and other immune-type receptors is not clear, nor is the relation of NITRs to several other large families of activating/inhibitory immunoglobulin-type receptors that have been identified in zebrafish as well as in cartilaginous fish.
Novel cloning strategies have been developed to identify immunoglobulin-type V regions in jawless vertebrates and in the more phylogenetically ancient protochordates, which lack immunoglobulins, T-cell antigen receptors, and MHC Class I and II and other features of conventional adaptive immune systems. Studies in this latter model have identified a particularly extensive family of receptors (VCBPs) that encode two tandem V regions and a chitin-binding tail. The solved crystal structure of one such VCBP localizes the primary site of genetic variation to a different surface of the V region fold from that used to form the antigen-combining site in immunoglobulin and T cell antigen receptors. VCBPs are expressed in cells lining the lumen of the gut and exhibit extremely high levels of interindividual variation at the genomic level. Ongoing efforts are focused on identifying the genetic mechanisms that diversify these receptors at the germline and somatic levels and the ligands recognized by these receptors. The long-term objective of these investigations is to understand relationships between the genetics of sequence variation and receptor function.