title: CTL are inactivated by herpes simplex virus-infected cells expressing a viral protein kinase.
abstract: Numerous cell-to-cell signals tightly regulate CTL function. Human fibroblasts infected with HSV type 1 or 2 can generate such a signal and inactivate human CTL. Inactivated CTL lose their ability to release cytotoxic granules and synthesize cytokines when triggered through the TCR. Inactivation requires cell-to-cell contact between CTL and HSV-infected cells. However, inactivated CTL are not infected with HSV. The inactivation of CTL is sustainable, as CTL function remains impaired when the CTL are removed from the HSV-infected cells. IL-2 treatment does not alter inactivation, and the inactivated phenotype is not transferable between CTL, distinguishing this phenotype from traditional anergy and T regulatory cell models. CTL inactivated by HSV-infected cells are not apoptotic, and the inactivated state can be overcome by phorbol ester stimulation, suggesting that inactivated CTL are viable and that the signaling block is specific to the TCR. HSV-infected cells require the expression of U(S)3, a viral protein kinase, to transmit the inactivating signal. Elucidation of the molecular nature of this signaling pathway may allow targeted manipulation of CTL function.
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Derek D
authors.initials: DD
authors.lastname: Sloan
authors.forename: George
authors.initials: G
authors.lastname: Zahariadis
authors.forename: Christine M
authors.initials: CM
authors.lastname: Posavad
authors.forename: Nichlos T
authors.initials: NT
authors.lastname: Pate
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Kussick
authors.forename: Keith R
authors.initials: KR
authors.lastname: Jerome
mesh_terms: D017209:Apoptosis / Q000276:immunology; D002460:Cell Line; D002461:Cell Line, Transformed; D002999:Clone Cells; D003513:Cycloheximide / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000528:radiation effects; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology* / Q000528:radiation effects; D004338:Drug Combinations; D005347:Fibroblasts / Q000276:immunology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000235:genetics / Q000276:immunology* / Q000528:radiation effects; D018258:Herpesvirus 2, Human / Q000187:drug effects / Q000235:genetics / Q000276:immunology* / Q000528:radiation effects; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology* / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D017384:Sequence Deletion; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000821:virology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014466:Ultraviolet Rays; D014764:Viral Proteins
chemical_list: D004338:Drug Combinations; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins; D015759:Ionomycin; D003513:Cycloheximide; D017346:Protein Serine-Threonine Kinases; C095207:US3 protein, Human herpesvirus 1; D013755:Tetradecanoylphorbol Acetate