Several of the most central, unsolved problems of immunobiology are how T-lymphocyte commitment, diversification and function arise during development. In a variety of developmental systems, such processes are associated with the accumulation of lineage-specific mRNAs and their protein products. Recently developed molecular approaches have provided the means by which to isolate, identify and study the expression and function of these developmentally important macromolecules. Based on this information, at least two experimentally testable hypotheses can be proposed regarding T-cell lineage commitment and maturation. 1. That there are multiple and as yet undescribed proteins encoded by lineage-specific mRNAs that accompany early commitment of cells to the T-cell lineage during development. 2. That there is a programmed, differential expression of such lineage-specific mRNAs in diverging cell types representing distinct stages in T-cell maturation and functional diversification. The first hypothesis will be approached by attempting to isolate such lineage-specific mRNAs from different developmental stages of thymocytes using the methods of subscription hybridization and cDNA cloning. The second hypothesis will be tested by mapping the expression patterns of lineage-specific mRNAs by in situ hybridization alone and in combination with immunocytologic staining. In further support of these studies and to provide a system in which to further study the expression and function of T- cell lineage-specific mRNAs and their encoded products, T-cell hybridomas will be generated from different organs during development to permit the clonal expansion of cultured cells that demonstrate stage-specific expression of lineage-restricted mRNAs. Such studies should significantly add to our understanding of the mRNAs and their products that accompany T-cell lineage commitment and diversification and thus to our knowledge of the development of host defense. The elucidation of such processes are furthermore central to any fundamental understanding of a variety of inherited immune deficiency diseases as well as how immune reconstitution occurs following bone marrow transplantation. Finally, the identification of such lineage-specific mRNAs and their expression patterns may provide a very useful approach to better classification of lymphoid malignancies.
Showing the most recent 10 out of 13 publications
