The enzyme dipeptidy peptidase IV (DPPIV) is an integral membrane protein which is widely distributed in mammalian tissues including liver, kidney, intestinal brush border membrane and placenta. DPPIV is also expressed at very low levels on a subset of resting T cells. The DPPIV positive T cells account for almost all IL-2 secretion and are important in initiating immunoglobulin synthesis by B cells. Recent evidence has been presented that the CD26 antigen of T cells is actually a DPPIV and that CD26 plays a key role in T cell activation. Much remains to be clarified regarding the complex functions of this protein in mammalian systems and its putative physiological substrates and/or ligands. The major goal of this proposal is to define the structural and functional relationships between the adhesion, ectoenzymatic and signal transducing functions of the human DPPIV/CD26 molecule. To accomplish this goal, we will first develop a large panel or monoclonal antibodies directed against different epitopes of DPPIV/CD26, including mAbs inhibiting DPPIV enzyme activity. These will be used as tools in identifying functionally important domains. Second, we will determine the role of DPPIV/CD26 in extracellular matrix-cell interactions and cell migration. Third, we will determine the function of DPPIV/CD26 in signal transduction and immune function utilizing CD26 transfected Jurkat leukemic T cell lines, a mutant CD26- H9 T cell line, and peripheral blood T cells as model systems. Fourth, we will prepare soluble recombinant DPPIV/CD26 molecules and determine their effects on various biological activities including cytokine production, cell adhesion, cell activation and migration. In addition, we will identify the natural substrates/ligands of DPPIV/CD26. Finally, we will determine the function and structure of the human DPPIV/CD26 association molecule, p43. The above information should help us to further understand the mechanisms of tumor invasion or metastasis, and the inflammatory process. Moreover, these studies may lead to the rational design of a novel class of drugs that act as specific antagonists or agonists in the regulation of cell adhesion, migration and signal transduction as well as other functions of DPPIV/CD26. This would have therapeutic implications for treatment of malignant tumors, autoimmune disorders, and immunodeficiency diseases such as AIDS.
