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Protein Kinase C Regulates Antigen Receptor-Induced Lytic Granule Polarization in Mouse CD8⁺ CTL¹

Jennifer S. Y. Ma^*, Ngozi Monu, David T. Shen^*, Ingrid Mecklenbräuker, Nadeda Radoja^¶, Tarik F. Haydar, Michael Leitges^2,||, Alan B. Frey, Stanislav Vukmanovi^* and Saa Radoja^3,*

^* Center for Cancer and Immunology and Center for Neuroscience, Children’s National Medical Center, Children’s Research Institute, Washington, DC 20010; Department of Cell Biology and Kaplan Cancer Center, New York University School of Medicine, New York, NY 10016; Laboratory of Lymphocyte Signaling, The Rockefeller University, New York, NY 10021; ^¶ Developmental Skin Biology Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892; and ^|| Max Planck Institute of Experimental Endocrinology, Hannover, Germany

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 PKC is required for granule exocytosis-mediated lytic function in mouse CD8⁺ T cells. Our studies demonstrate that PKC 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 PKC-deficient cytotoxic lymphocytes is reversed by ectopic expression of PKC. Finally, we show that PKC 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 PKC as a novel and selective regulator of Ag receptor-induced lytic granule polarization in mouse CD8⁺ T cells.

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 National Institutes of Health Grant R01 CA108573 (to A.B.F.), National Institutes of Health Grant F32CA101449-02 Award and Research Advisory Council Grant (to S.R.), and National Institutes of Health Grants R01AI48837 and R01AI41573 (to S.V.).

² Requests for PKC-deficient mice should be sent to michael.leitges@biotek.uio.no

³ Address correspondence and reprint requests to Dr. Sasa Radoja, Center for Cancer and Immunology, Children’s Research Institute, Children’s National Medical Center, 111 Michigan Avenue, NW Washington, DC 20010. E-mail address: sradoja{at}cnmc.org

⁴ Abbreviations used in this paper: MTOC, microtubule-organizing center; PKC, protein kinase C; IRES, internal ribosome entry site; WT, wild type; RGGTA, Rab geranylgeranyl transferase; FHL, familial hemophagocytic lymphohistiocytosis.

⁵ The online version of this article contains supplemental material.

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