T cell-mediated cytotoxicity: Understanding the mechanism of effective delivery of a poison pill

Cytotoxic T lymphocytes (CTL) are an instrumental part of the immune response against pathogens, viruses in particular. CTL can kill virus infected target cells upon triggering of the T cell antigen receptor (TCR) with virus-derived peptides presented by major histocompatibility complex (MHC) molecules on the surface of the infected cell. The killing of the infected cells is primarily mediated by the release of soluble molecules contained within membrane-bound vesicles or lytic ganules, often referred to as poison pills, from the CTL. The lytic granules are released directionally from the CTL to the bound target cell at the cellular contact, called the immunological synapse (IS). In the current work, we compared more (CD8+) and less (CD4+) effective CTL to understand the molecular events during the formation of the IS that promote efficient release of the lytic granules and target cell destruction. We found that the formation of a stable peripheral adhesive ring, pSMAC, by CTL functions as a gasket to ensure that the molecules released from the lytic granules are contained to the synaptic contact for effective target cell lysis. The stability of this peripheral adhesive ring was partly controlled by the signaling molecule protein kinase C &thetas; (PKC &thetas;). Furthermore, we demonstrate that efficient lytic granule targeting to the center of the synapse depends on the strength of TCR stimulation. This central location of the lytic granules at the IS appears to facilitate a swift rate of granule release and faster kinetics of target cell lysis. The findings described herein unveil novel mechanisms that are used by CTL to facilitate efficient release of the granules and effective target cell destruction. These findings have important implications for the development of improved anti-viral immunotherapies in the future