title: Involvement of classical and novel protein kinase C isoforms in the response of human V gamma 9V delta 2 T cells to phosphate antigens.
abstract: Human gammadelta T cells expressing the Vgamma9Vdelta2 gene segments are activated polyclonally by phosphoantigens found on a wide variety of pathogenic organisms. After ligand exposure, Vgamma9Vdelta2 T cells proliferate and rapidly secrete large amounts of cytokines and chemokines that contribute to the innate immune response to these pathogens. Neither APCs nor costimulatory molecules are required. In this study we examined whether these phosphoantigens activate protein kinase Ctheta (PKCtheta). This novel PKC isoform is essential for Ag signaling through the alphabeta TCR in a costimulation-dependent fashion. The results showed that isopentenyl pyrophosphate (IPP), a soluble phospholigand released by mycobacteria, led to the rapid and persistent activation of PKCtheta in gammadelta T cells, as determined by evidence of translocation and phosphorylation. In contrast, no ligand-dependent response was detected for PKCalpha/beta or PKCdelta. Using the inhibitors Gö6976 and rottlerin, a role for both conventional and novel PKC isoforms in IPP-induced proliferation, CD25 expression, and cytokine and chemokine production was demonstrated. Gel-shift assays indicated that the transcription factors NF-kappaB and AP-1 were downstream targets of PKC activation. IPP also induced the rapid and persistent phosphorylation of extracellular signal-regulated kinases 1 and 2, p38 mitogen-activated kinase, and stress-activated kinase/c-Jun N-terminal kinase, but only an inhibitor of conventional PKCs blocked these responses. We conclude that the gammadelta T cell response to phosphoantigens is regulated by both novel and conventional PKC isoforms, with PKCtheta being more responsive to ligand stimulation and PKCalpha/beta to growth-factor availability.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cipriani
authors.forename: Heather
authors.initials: H
authors.lastname: Knowles
authors.forename: Lanfen
authors.initials: L
authors.lastname: Chen
authors.forename: Luca
authors.initials: L
authors.lastname: Battistini
authors.forename: Celia F
authors.initials: CF
authors.lastname: Brosnan
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000942:Antigens, Bacterial / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D045782:Hemiterpenes; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology*; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D000074121:Protein Kinase C-theta; D021381:Protein Transport / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000098:Acetophenones; D000942:Antigens, Bacterial; D001578:Benzopyrans; D002227:Carbazoles; D018925:Chemokines; D016207:Cytokines; D045782:Hemiterpenes; D007211:Indoles; D007527:Isoenzymes; D009943:Organophosphorus Compounds; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014157:Transcription Factors; C081021:Go 6976; C004809:isopentenyl pyrophosphate; C085746:rottlerin; C496628:PRKCA protein, human; C497258:PRKCD protein, human; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D000074121:Protein Kinase C-theta