Protein Kinase Cδ Regulates Antigen Receptor-Induced Lytic Granule Polarization in Mouse CD8+ CTL

Lytic granule exocytosis is the major pathway used by CD8+ CTL to kill virally infected and tumor cells. Despite the obvious importance of this pathway in adaptive T cell immunity, the molecular identity of enzymes involved in the regulation of this process is poorly characterized. One signal known to be critical for the regulation of granule exocytosis-mediated cytotoxicity in CD8+ T cells is Ag receptor-induced activation of protein kinase C (PKC). However, it is not known which step of the process is regulated by PKC. In addition, it has not been determined to date which of the PKC family members is required for the regulation of lytic granule exocytosis. By combination of pharmacological inhibitors and use of mice with targeted gene deletions, we show that PKCδ is required for granule exocytosis-mediated lytic function in mouse CD8+ T cells. Our studies demonstrate that PKCδ is required for lytic granule exocytosis, but is dispensable for activation, cytokine production, and expression of cytolytic molecules in response to TCR stimulation. Importantly, defective lytic function in PKCδ-deficient cytotoxic lymphocytes is reversed by ectopic expression of PKCδ. Finally, we show that PKCδ is not involved in target cell-induced reorientation of the microtubule-organizing center, but is required for the subsequent exocytosis step, i.e., lytic granule polarization. Thus, our studies identify PKCδ as a novel and selective regulator of Ag receptor-induced lytic granule polarization in mouse CD8+ T cells.