DIFFERENTIAL-EFFECTS OF CYCLIC ADENOSINE-3',5'-MONOPHOSPHATE ON T-CELL CYTOTOXICITY

We have investigated natural killer cell and T cell cytotoxicity using different assays and report a dual effect of cyclic adenosine 3',5'-monophosphate (cAMP) on T cell cytotoxicity depending on the activation status of the effector cell and the test system in question. cAMP enhanced the capacity of pre-activated T cells to induce DNA fragmentation in the target cell, while it inhibited spontaneous T cell cytotoxicity and natural killer cell cytotoxicity in conventional assays based on Cr-51 release. The enhancement was most likely mediated by the cAMP-dependent protein kinase type II (cAKII), which is the particular isoform in T cells associated with the centrosome and the microtubule organizing center (MTOC). We show the complete co-localization of the cAKII with the centrosome after conjugate formation. Furthermore, the reorganization of the MTOC following conjugate formation brings the type II kinase into close proximity with the T lymphocyte membrane area engaged in the effector-target interaction. Functional studies utilizing different cAMP-analog combinations further substantiate the involvement of the type II kinase.