This program examines the genetics, dynamics, and control of antibody repertoire formation. First, the influenza hemagglutinin (HA) and phosphorylcholine (PC) specific repertoires will be examined in various inbred, recombinant inbred, and congenic strains of mice. These studies will allow assessment of the number and linkage relationships of loci which control repertoire ontogeny. Dynamics of repertoire composition, in terms of clonotypes present, will be determined by defining these repertoires at several ages during early life. Clonotype identification will be any reactivity pattern or idiotypic analysis of monoclonal antibodies derived from limiting dilution cultures. Either splenic fragment culture or alternative limiting dilution techniques developed in this project will be employed. Whether the dynamics of clonotype appearance and turnover are due to constitutive or induced T-cell regulation will be assessed by similar studies of nu/nu athymic mice. The effect of ligand exposure upon the emerging primary repertoire will be assessed by characterizing the HA-responsive repertoire in animals exposed to virus. If pronounced effects are observed, their cellular requirements, specificity, and longevity will be assessed. In addition, adoptive transfer of putative regulatory cell populations will be performed to determine whether such cellular regulators of repertoire formation can act at all B-cell differentiation stages, or whether their effects upon repertoire formation differ depending upon the time of their emergence (or introduction). Finally, high-efficiency limiting dilution systems which provide definitive analysis of all input cell populations will be explored.
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