The extended objective of this proposal is to examine the molecular and genetic mechanisms governing lymphocyte circulation and their relationship to murine lymphocyte and lymphoid tumor endothelial cell recognition. Lymphocyte circulation through the peripheral lymph nodes and Peyer's patches is dependent upon the expression of two distinct developmentally regulated receptor systems (one specific for peripheral lymph node, one specific for Peyer's patches) responsible for the adhesion of lymphocytes to the high endothelial (HE) cells of the lymph organ postcapillary venules. The monoclonal antibody MEL-14, specific for the lymphocyte cell surface high endothelial venule receptor structure, has been successfully used to isolate the gene sequences encoding a portion of the peripheral lymph node receptor. These sequences encode ubiquitin; we have also collected amino acid sequence data that supports this finding, as well as evidence for a second polypeptide chain within the receptor structure. The isolation of the DNA sequences encoding this portion of the receptor structure will be achieved by either immunological or nucleic acid hybridization techniques. Monoclonal antibodies will be prepared to the native cell surface molecule (and/or the cloned DNA sequences expressed as bacterial fusion proteins). The genomic structure and the expression of these DNA sequences as both transcripts and cell surface proteins will be examined. The functional consequences of the expression (and misexpression) of these gene sequences in normal tissues, lymphoid tumors and DNA transfectants will be examined. The expression of HEV receptors may contribute to the metastatic potential of lymphoid tumors; an understanding of the molecular basis of this potential may allow more reliable prognosis and treatment of these tumors. This model cell recognition system is one of the best characterized, most thoroughly validated (in vivo and in vitro) examples of specific cell interactions between lymphoid and nonlymphoid cells. The mechanisms responsible for this interaction may provide general models applicable to many aspects of tissue development.
