title: Protein kinase C theta regulates stability of the peripheral adhesion ring junction and contributes to the sensitivity of target cell lysis by CTL.
abstract: Destruction of virus-infected cells by CTL is an extremely sensitive and efficient process. Our previous data suggest that LFA-1-ICAM-1 interactions in the peripheral supramolecular activation cluster (pSMAC) of the immunological synapse mediate formation of a tight adhesion junction that might contribute to the sensitivity of target cell lysis by CTL. Herein, we compared more (CD8(+)) and less (CD4(+)) effective CTL to understand the molecular events that promote efficient target cell lysis. We found that abrogation of the pSMAC formation significantly impaired the ability of CD8(+) but not CD4(+) CTL to lyse target cells despite having no effect of the amount of released granules by both CD8(+) and CD4(+) CTL. Consistent with this, CD4(+) CTL break their synapses more often than do CD8(+) CTL, which leads to the escape of the cytolytic molecules from the interface. CD4(+) CTL treatment with a protein kinase Ctheta inhibitor increases synapse stability and sensitivity of specific target cell lysis. Thus, formation of a stable pSMAC, which is partially controlled by protein kinase Ctheta, functions to confine the released lytic molecules at the synaptic interface and to enhance the effectiveness of target cell lysis.
authors.affiliation: Department of Microbiology and Immunology and Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Beal
authors.forename: Nadia
authors.initials: N
authors.lastname: Anikeeva
authors.forename: Rajat
authors.initials: R
authors.lastname: Varma
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Cameron
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Norris
authors.forename: Michael L
authors.initials: ML
authors.lastname: Dustin
authors.forename: Yuri
authors.initials: Y
authors.lastname: Sykulev
mesh_terms: D000595:Amino Acid Sequence; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D002448:Cell Adhesion / Q000276:immunology; D002449:Cell Aggregation / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D002461:Cell Line, Transformed; D002999:Clone Cells; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D004795:Enzyme Stability / Q000276:immunology; D015488:HIV Antigens / Q000276:immunology / Q000378:metabolism; D006801:Humans; D054992:Immunological Synapses / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D009980:Influenza A virus / Q000276:immunology; D007527:Isoenzymes / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology; D008969:Molecular Sequence Data; D011493:Protein Kinase C / Q000502:physiology*; D000074121:Protein Kinase C-theta; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology* / Q000276:immunology* / Q000821:virology; D014763:Viral Matrix Proteins / Q000276:immunology / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D015488:HIV Antigens; D007527:Isoenzymes; C031540:M-protein, influenza virus; D014763:Viral Matrix Proteins; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta
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