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Localizes to Secretory Lysosomes in CD8+ CTL and Directly Mediates TCR Signals Leading to Granule Exocytosis-Mediated Cytotoxicity1
a Radoja2,*
* Center for Cancer and Immunology and
Center for Neuroscience, Children’s National Medical Center, Children’s Research Institute, Washington, DC 20010
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 
(PKC ) selectively regulates TCR-induced lytic granule polarization in mouse CD8+ CTL. To better understand how PKC facilitates granule movement, here we studied dynamics of intracellular localization of PKC in living CD8+ CTL. Strikingly, we found that PKC 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 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 , providing the first example of colocalization of a kinase with secretory lysosomes in CD8+ CTL and demonstrating that PKC directly transduces TCR signals leading to polarized granule secretion.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Avery Award (to S.R.).
2 Address correspondence and reprint requests to Dr. Saa Radoja, Children’s National Medical Center, Center for Cancer and Immunology, Children’s Research Institute, 111 Michigan Avenue, NW Washington, DC 20010. E-mail address: sradoja{at}cnmc.org
3 Abbreviations used in this paper: MTOC, microtubule-organizing center; PKC, protein kinase C; KN, kinase-negative; WT, wild type.
4 The online version of this article contains supplemental material.
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