Lymphocytes are the central recognition elements of the immune response. They are divided into 2 major classes - T and B cells - and each of these are further subdivided into functional and phenotypic subclasses. A major goal of this grant is to define the full maturation sequence of both T and B cell lineages, from effector cells back to a hematopoietic stem cells. New methods of clonging pre-B and pre-T cells will be combined with 3-color FACS sorting and clonal functional analyses to define stages and microenvironments wherein these cells commit to antigen receptor expression, homing receptor expression, function, phenotype, self-nonself discrimination, and MHC restricted recognition of antigens. At each stage of differentiation the regulation of expression of cloned T and B cell specific genes shall also be examined, including the rearrangement, transcription, and class-switching of immunoglobulin and T cell receptor genes. A second major goal is to identify the homing patterns of defined subsets of lymphocytes. Two have been defined (for lymph node high endothelial venules (HEV) and Peyer's patch HEV) by function and specific anti-receptor monoclonal antibodies. The lymph node receptor is a branched-chain polypeptide whose amino acid sequence we know. In this grant three other biological homing properties will be studied -BAlpha immunoblasts to gut lamina propria, TC and TD homing to target antigen sites, and pre-T cells to the thymus. An eventual aim is to identify a family of homing receptors, clone their genes, and test their function. A second major aim is to define the role of homing receptors in metastasis of lymphoid tumors. Two aspects of oncogenesis shall be studied: The Receptor Mediated Leukemogenesis Hypothesis will be tested directly to determine if leukemogenic retroviruses bind to antigen receptors on T and B cells a) to infect and transform them, and b) to stimulate their entry into the mitotic cycle. The second aspect of oncogenesis studied will be the role of 6C3Ag - B-lineage transformation specific molecule on all mouse pre-B/early B cell lymphomas - in normal and neoplastic B cell maturation. 6C3Ag is present also on cloned bone marrow stromal elements which support the growth and maturation of pre-B cells. In this grant we shall test the hypothesis that 6C3Ag is a cell surface growth and/or differentiation factor for early pre-B lineage cells, and that neoplastic development is the inappropriate expression of this gene in cells bearing receptors for its products (Receptor Mediated Leukemogenesis). Finally, to study the evolutionary antecedents to the co-evolving MHC and T cells which recognize it, this grant will also identify in the highest invertebrates - the Protochordates - the polymorphic genes and products involved in natural allorecognition in the wild, and whether these are encoded by genes hybridizing to vertebrate MHC and Thy-1 genes.
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