Protein Kinase C δ Localizes to Secretory Lysosomes in CD8+ CTL and Directly Mediates TCR Signals Leading to Granule Exocytosis-Mediated Cytotoxicity

Abstract

Lytic granule exocytosis is the major effector function used by CD8+ CTL in response to intracellular pathogens and tumors. Despite recent progress in the field, two important aspects of this cytotoxic mechanism remain poorly understood. First, TCR-signaling pathway(s) that selectively induces granule exocytosis in CTL has not been defined to date. Second, it is unclear how Ag receptor-induced signals are converted into mobilization of lytic granules. We recently demonstrated that protein kinase C δ (PKC δ) selectively regulates TCR-induced lytic granule polarization in mouse CD8+ CTL. To better understand how PKC δ facilitates granule movement, here we studied dynamics of intracellular localization of PKC δ in living CD8+ CTL. Strikingly, we found that PKC δ localizes to the secretory lysosomes and polarizes toward immunological synapse during the process of target cell killing. Also, biochemical and structure-function studies demonstrated that upon TCR ligation, PKC δ becomes rapidly phosphorylated on the activation loop and regulates granule exocytosis in a kinase-dependent manner. Altogether, our current studies provide new insights concerning the regulation of TCR-induced lytic granule exocytosis by revealing novel intracellular localization of PKC δ, providing the first example of colocalization of a kinase with secretory lysosomes in CD8+ CTL and demonstrating that PKC δ directly transduces TCR signals leading to polarized granule secretion.