Prevention of antigen-induced microtubule organizing center reorientation in cytotoxic T cells by modulation of protein kinase C activity.
Lysis of target cells (TC) by cytotoxic T lymphocytes (CTL) is achieved by directional exocytosis of cytolytic molecules-perforin and granzymes. They are stored within lytic granules which can be readily released following antigenic stimulation. Secretion of lytic molecules appears to be controlled by protein kinase C (PKC) activity, since specific modulators of PKC activity abolish the lysis of TC. We have examined the effect of PKC modulation on some of the earliest events in the perforin/granzyme-mediated cytotoxicity. De novo synthesis of perforin mRNA, required for the refilling of granules and sustained cytotoxicity, seems to be unaltered in the presence of PKC modulators. Immunofluorescent studies of CTL-TC conjugates revealed that PKC modulation impairs reorientation of the microtubule organizing center toward the contact point with the TC, which accounts for the specific direction of lytic granules exocytosis. Thus, it appears that PKC regulates exocytosis of lytic granules by governing microtubule reorganization, one of the initial steps in perforin/granzyme-mediated cytotoxicity.
Nesić
D
D
Department of Pathology and Kaplan Cancer Center, NYU Medical Center, New York, NY 10016, USA.
Henderson
S
S
Vukmanović
S
S
D000818:Animals; D054713:Bryostatins; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D005089:Exocytosis / Q000502:physiology; D005455:Fluorescent Antibody Technique; D007783:Lactones / Q000494:pharmacology; D018942:Macrolides; D008562:Membrane Glycoproteins / Q000378:metabolism; D008870:Microtubules / Q000502:physiology*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000648:ultrastructure
D054713:Bryostatins; D007783:Lactones; D018942:Macrolides; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger; D054353:Perforin; C046785:bryostatin 1; D011493:Protein Kinase C