title: Protein kinase C-theta-mediated signals enhance CD4+ T cell survival by up-regulating Bcl-xL.
abstract: Productive engagement of TCR results in delivering signals required for T cell proliferation as well as T cell survival. Blocking TCR-mediated survival signals, T cells undergo apoptosis instead of proliferation upon TCR stimulation. During the activation process, T cells produce IL-2, which acts as an extrinsic survival factor. In addition, TCR stimulation results in up-regulation of Bcl-xL to enhance T cell survival intrinsically. We show in this study that protein kinase C (PKC)-theta is required for enhancing the survival of activated CD4+ T cells by up-regulating Bcl-xL. In response to TCR stimulation, CD4+ PKC-theta-/- T cells failed to up-regulate Bcl-xL, and underwent accelerated apoptosis via a caspase- and mitochondria-dependent pathway. Similar to PKC-theta-deficient primary CD4+ T cells, small interfering RNA-mediated knockdown of PKC-theta in Jurkat cells also resulted in apoptosis upon TCR stimulation. Forced expression of Bcl-xL was sufficient to inhibit apoptosis observed in PKC-theta knockdown cells. Furthermore, ectopic expression of PKC-theta stimulated a reporter gene driven by a mouse Bcl-xL promoter. Whereas an inactive form of PKC-theta or knockdown of endogenous PKC-theta led to inhibition of Bcl-xL reporter. PKC-theta-mediated activation of Bcl-xL reporter was inhibited by dominant-negative IkappaB kinase beta or dominant-negative AP-1. Thus, the PKC-theta-mediated signals may function not only in the initial activation of naive CD4+ T cells, but also in their survival during T cell activation by regulating Bcl-xL levels through NF-kappaB and AP-1 pathways.
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Illinois, Chicago, IL 60612, USA.
authors.forename: Santhakumar
authors.initials: S
authors.lastname: Manicassamy
authors.forename: Sonal
authors.initials: S
authors.lastname: Gupta
authors.forename: Zhaofeng
authors.initials: Z
authors.lastname: Huang
authors.forename: Zuoming
authors.initials: Z
authors.lastname: Sun
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D053148:Caspase 3; D020169:Caspases / Q000502:physiology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D017930:Genes, Reporter; D006801:Humans; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology / Q000276:immunology; D016328:NF-kappa B / Q000502:physiology; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000074121:Protein Kinase C-theta; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D051020:bcl-X Protein / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C494812:Bcl2l1 protein, mouse; D007527:Isoenzymes; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D051020:bcl-X Protein; C076233:PRKCQ protein, human; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases