EVOLUTION OF ADAPTIVE IMMUNITY

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Immunoglobulin (Ig) and the T cell receptor (TCR) are the only antigen- specific receptors of the adaptive immune system that have been extensively characterized. We have discovered a novel antigen receptor in the nurse shark, Ginglymostoma cirratum, that diverged from the Ig/TCR line perhaps near the time of the conception of the adaptive immune system. This molecule, referred to as NAR (novel antigen receptor) is dimeric in serum and on the cell surface, with each chain being composed of an N-terminal V domain followed by 5 C domains. The complementarity determining region 3 (CDR3) of NAR is incredibly diverse in sequence and length, in part apparently due to "oligonucleotide capture" during the joining process. There is also a very high frequency of somatic mutation (up to 12% in cDNA clones that have been analyzed) concentrated in the CDR. The hypothesis is that NAR is found on the surface of cells in the shark (and perhaps other vertebrates) that are instrumental in generating secondary responses, and that such cells may be homologous to "secondary B cells described in mammalian systems. The study of this molecule (and its gene) is significant to: l) understand selection pressures on antigen specific receptors forcing them to adopt particular conformations; 2) provide a model to examine secondary immune responses; 3) supply, in the long term, a. novel system to study somatic mutation and "oligonucleotide capture." NAR will be examined at the cellular, biochemical, molecular, functional, and phylogenetic levels with existing specific antibodies and gene probes. The Specific Aims are: 1) to determine which cell types express NAR and to observe whether other antigen receptors (like IgM or TCR) are excluded from such cells; 2) to study the biochemical structure of NAR, concentrating on associated receptors and the role of D-region encoded protein in maintenance of the NAR fold; 3) a continued analysis of somatic mutation and potential "oligonucleotide capture" in the joining regions; 4) to study the function of NAR to determine whether T-dependent affinity maturation occurs after immunization, and to examine the significance of the somatic mutation; and 5) to search for NAR's presence in diverse vertebrates to further evaluate its structure/function. It is likely that NAR will be the first characterized novel antigen recognition molecule in a long line awaiting discovery.