Dissection of signals controlling T cell function and activation: H7, an inhibitor of protein kinase C, blocks induction of primary T cell proliferation by suppressing interleukin (IL) 2 receptor expression without affecting IL 2 production

摘要

AbstractT cell activation induced via cross‐linking of the T cell receptor (TcR) stimulates hydrolysis of phosphatidylinositol to the second messengers diacylglycerol (DAG) and inositol 1,4,5‐triphosphate (IP3). DAG is necessary for the activation and function of protein kinase C (PKC) which is suggested to play a key role in the cascade of signal transduction when translocated from the cytosol to the cell membrane. In this report, we investigated responses of restingvs. activated Ly‐2+and L3T4+T lymphocytes in the presence of the PKC inhibitor H7 1‐(5‐isoquinolinylsulfonyl)‐2‐methylpiperazine. H7 inhibited the induction of primary T cell proliferation, while interleukin 2 (IL 2) production was fully retained. The effect of the PKC inhibitor on primary T cells depended on the type of ligand interacting with the TcR: increasing doses of concanavalin A or of immobilized anti‐CD3 monoclonal antibody (mAb), but not of anti‐Vβ8 or of anti‐TcR α/β mAb, partly overcame the blockade, indicating a differential signaling compared to the former stimuli. The blockade of T cell proliferation by H7 was not due to an inhibition of PKC translocation, but occurred even 4–8 h after T cell induction and correlated with a significant reduction of IL 2 receptor (IL 2R) expression. In contrast, the mRNA levels of IL 2R and the cellular proto‐oncogenes c‐fos and c‐myc were not affected. On activated T cells, H7 neither blocked proliferation nor IL 2R expression. Consequently, H7 dissects the signal resulting in T cell proliferation from those governing the triggering of other T cell functions,i.e.IL 2 production, during primary responses of Ly