Human T cell activation and proliferation have been probed by monoclonal antibodies in the presence of phorbol myristate acetate (PMA). An early activation antigen (EA 1) which was expressed by medullary thymocytes but not by peripheral blood T cells was induced rapidly by PMA and synthetic diacylglycerol. In addition, CD28 (9.3) has been defined to mediate an activation pathway. In this proposal, studies are proposed to extend these findings.
Five Aims are proposed. (1) Because of its rapid expression and the ease of detecting factors potentiating its expression, we wish to define the role of monokines in the potentiation of EA 1 expression and to identify novel monokines active on T cells. (2) To compare the activation requirements for EA 1 induction in T and B cells and to relate these findings to the expression of protein kinase C isoenzymes. (3) To clone and to express the genes encoding the major 22Kd deglycosylated peptide in the EA 1 complex so that the function of EA 1 can be studied further. (4) To further define the CD28 pathway by comparing it to the CD3/Ti pathway. (5) To ascertain whether CD28 is a receptor molecule involved in cell-cell interaction or a potential receptor for a yet to be defined cytokine. Parts of these studies will be carried out with CD28 isolated from cells. To facilitate recombinant CD28 with these studies, extracellular domains only will be generated so that sufficient amounts of CD28 are available for detailed studies. These studies will identify potential interactive surface molecules important for T cell activation. They may also provide some insights into the monocyte related activation mechanisms, some of which are defective in diseases with immunological deficiencies.
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