title: Protein kinase C (PKC) alpha and PKC theta are the major PKC isotypes involved in TCR down-regulation.
abstract: It is well known that protein kinase C (PKC) plays an important role in regulation of TCR cell surface expression levels. However, eight different PKC isotypes are present in T cells, and to date the particular isotype(s) involved in TCR down-regulation remains to be identified. The aim of this study was to identify the PKC isotype(s) involved in TCR down-regulation and to elucidate the mechanism by which they induce TCR down-regulation. To accomplish this, we studied TCR down-regulation in the human T cell line Jurkat, in primary human T cells, or in the mouse T cell line DO11.10 in which we either overexpressed constitutive active or dominant-negative forms of various PKC isotypes. In addition, we studied TCR down-regulation in PKC knockout mice and by using small interfering RNA-mediated knockdown of specific PKC isotypes. We found that PKCalpha and PKCtheta were the only PKC isotypes able to induce significant TCR down-regulation. Both isotypes mediated TCR down-regulation via the TCR recycling pathway that strictly depends on Ser(126) and the di-leucine-based receptor-sorting motif of the CD3gamma chain. Finally, we found that PKCtheta was mainly implicated in down-regulation of directly engaged TCR, whereas PKCalpha was involved in down-regulation of nonengaged TCR.
authors.affiliation: Institute of Medical Microbiology and Immunology, University of Copenhagen, Denmark.
authors.forename: Marina
authors.initials: M
authors.lastname: von Essen
authors.forename: Martin W
authors.initials: MW
authors.lastname: Nielsen
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Bonefeld
authors.forename: Lasse
authors.initials: L
authors.lastname: Boding
authors.forename: Jeppe M
authors.initials: JM
authors.lastname: Larsen
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.forename: Gottfried
authors.initials: G
authors.lastname: Baier
authors.forename: Niels
authors.initials: N
authors.lastname: Odum
authors.forename: Carsten
authors.initials: C
authors.lastname: Geisler
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D017252:CD3 Complex / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D006801:Humans; D006825:Hybridomas; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019169:Jurkat Cells; D007930:Leucine / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051571:Protein Kinase C-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000074121:Protein Kinase C-theta; D034741:RNA, Small Interfering / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*
chemical_list: D017252:CD3 Complex; C452842:CD3 antigen, gamma chain; D007527:Isoenzymes; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; C496630:Prkca protein, mouse; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D000074121:Protein Kinase C-theta; D007930:Leucine