Protein Kinase Cθ Regulates Stability of the Peripheral Adhesion Ring Junction and Contributes to the Sensitivity of Target Cell Lysis by CTL

Abstract Destruction of virus-infected cells by CTL is an extremely sensitive and efficient process. Our previous data suggest that LFA-1-ICAM-1 interactions in the peripheral supramolecular activation cluster (pSMAC) of the immunological synapse mediate formation of a tight adhesion junction that might contribute to the sensitivity of target cell lysis by CTL. Herein, we compared more (CD8+) and less (CD4+) effective CTL to understand the molecular events that promote efficient target cell lysis. We found that abrogation of the pSMAC formation significantly impaired the ability of CD8+ but not CD4+ CTL to lyse target cells despite having no effect of the amount of released granules by both CD8+ and CD4+ CTL. Consistent with this, CD4+ CTL break their synapses more often than do CD8+ CTL, which leads to the escape of the cytolytic molecules from the interface. CD4+ CTL treatment with a protein kinase Cθ inhibitor increases synapse stability and sensitivity of specific target cell lysis. Thus, formation of a stable pSMAC, which is partially controlled by protein kinase Cθ, functions to confine the released lytic molecules at the synaptic interface and to enhance the effectiveness of target cell lysis.