Members of the immunoglobulin gene superfamily (IgSF) mediate innate and adaptive immunity in jawed vertebrates. Diversity of the IgSF-innate immune receptors is maintained in the germline, whereas adaptive receptors derive unique recognition function through somatic rearrangement and other modifications of immune genes in individual cells. The evolutionary origins of the rearranging IgSF receptors that mediate adaptive immunity is hypothesized to have occurred after the divergence of jawless and jawed vertebrate forms. However, the nature of the innate receptor from which the ancestral adaptive immune receptor derived is not understood, nor are the origins and patterns of divergence of the complex IgSF families, such as the activating/inhibitory leukocyte regulatory receptors, that mediate different innate immune functions. Major voids in understanding immune receptor diversification will be filled by characterizing the structure and function of IgSF genes in species representing critical early branch points in chordate evolution, including: 1) a highly diversified family of activating/inhibitory IgSF receptors in cartilaginous fish, 2) several immune-type IgSF genes in a jawless vertebrate, and 3) a multigene family encoding diversified IgSF related variable regions in a protochordate. The genetic basis for receptor diversity will be defined, the cell lineages expressing the receptors will be identified and potential receptor-ligand interactions will be characterized. Although the questions posed by each of the model systems require different approaches for gene discovery and characterization, several novel technologies are common to the various projects, including: 1) a highly efficient cloning method that requires knowledge of only a single short peptide motif, 2) unique soluble chimeric receptor constructs, and 3) a sensitive GFP-coupled reporter assay. In addition, methods used in studies of natural killer function and pathogen isolation will be adapted to these investigations. This broad-based approach will define the fundamental mechanisms that underlie the evolutionary divergence of the IgSF immune effectors and identify heretofore, unrecognized genetic and functional relationships between adaptive and innate immunity. Such information is fundamental to understanding the basis for self-nonself discrimination and how structural diversification relates to immune specificity.
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