Protein Kinase C-θ-Mediated Signals Enhance CD4+ T Cell Survival by Up-Regulating Bcl-xL

Manicassamy, Santhakumar; Gupta, Sonal; Huang, Zhaofeng; Sun, Zuoming

doi:10.4049/jimmunol.176.11.6709

Cited by 65 publications

(87 citation statements)

References 44 publications

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“…This defect reflects the deficient activation of the transcription factors NF-B, AP-1, and NF-AT (3)(4)(5), consistent with observations that PKC, but not other T cell-expressed PKCs, activate the corresponding reporter genes in T cells (6). In addition, PKC is essential for T cell survival, modulating the expression or activity of Bcl-2 family members (7)(8)(9)(10).…”

supporting

confidence: 56%

“…For Transwell experiments, isolated NK cells and NK-depleted splenocytes were placed, respectively, in the upper and lower chambers of a 24-well Transwell plate in the presence or absence of poly(I:C) during 16 h. Then, NK cells were recovered for Western blot analysis. Finally, for IL-12 and IL-15 time course experiments, 10 5 purified NK cells were cultured in the presence of 100 ng/ml mouse rIL-12 (Invitrogen) or IL-15 (Calbiochem) during the times indicated, and both PKC expression and phosphorylation were analyzed as indicated above.…”

Section: Analysis Of Pkc Activation and Expression In Nk Cellsmentioning

confidence: 99%

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Protein Kinase C-θ Is Required for NK Cell Activation and In Vivo Control of Tumor Progression

Aguilo

Garaude

Pardo

et al. 2009

The Journal of Immunology

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Protein kinase C-θ (PKCθ) was initially isolated as an important PKC isoform expressed in T cells, although its expression is not restricted to these cells. Despite the central function of PKCθ in several immune responses, its role in the antitumor response against MHC class I (MHC-I)-negative cells has not been investigated. This is an important issue because most tumor cells growing in vivo down-regulate MHC-I expression to escape the CTL-mediated response. In the present work, we show that in vivo development of a MHC-I-deficient tumor (RMA-S) is much favored in PKCθ−/− mice compared with wild-type mice. This is associated with a reduced recruitment of NK cells to the site of tumor development and a reduced activation status of recruited NK cells. This correlates with a reduced ex vivo and in vivo cytotoxic potential of NK cells isolated from PKCθ−/− mice treated with polyinosinic:polycytidylic acid. Consistently, polinosinic:cytidilic acid treatment induces PKCθ expression and activation of its enzymatic activity in NK cells in an indirect manner. These observations underline the relevance of PKCθ as a key molecule in NK cell-mediated antitumor immune surveillance.

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supporting

confidence: 56%

Section: Analysis Of Pkc Activation and Expression In Nk Cellsmentioning

confidence: 99%

Protein Kinase C-θ Is Required for NK Cell Activation and In Vivo Control of Tumor Progression

Aguilo

Garaude

Pardo

et al. 2009

The Journal of Immunology

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“…PKC has been shown to modulate the activities of many transcription factors including nuclear factor of activated T cell c2, NF-B, and activator protein-1 (47), and several lines of evidence indicate PKC to also be involved in transcriptional repression by modulating nuclear receptor-corepressor and/or -coactivator interaction in T lymphoid cells (48) (49). Because significant increases in caspase-3 activity were detected in C2C12 myotubes exposed to saturated FFAs but not unsaturated FFAs, the suppression of sortilin mRNA expression observed herein might be a consequence of apoptotic responses to some degree.…”

Section: Discussionmentioning

confidence: 99%

Palmitate-induced Down-regulation of Sortilin and Impaired GLUT4 Trafficking in C2C12 Myotubes

Tsuchiya

Hatakeyama

Emoto

et al. 2010

Journal of Biological Chemistry

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Elevated saturated FFAs including palmitate (C16:0) are a primary trigger for peripheral insulin resistance characterized by impaired glucose uptake/disposal in skeletal muscle, resulting from impaired GLUT4 translocation in response to insulin. We herein demonstrate that palmitate induces down-regulation of sortilin, a sorting receptor implicated in the formation of insulin-responsive GLUT4 vesicles, via mechanisms involving PKC and TNF-␣-converting enzyme, but not p38, JNK, or mitochondrial reactive oxygen species generation, leading to impaired GLUT4 trafficking in C2C12 myotubes. Intriguingly, unsaturated FFAs such as palmitoleate (C16:1) and oleate (C18:1) had no such detrimental effects, appearing instead to effectively reverse palmitate-induced impairment of insulin-responsive GLUT4 recycling along with restoration of sortilin abundance by preventing aberrant PKC activation. On the other hand, shRNA-mediated reduction of sortilin in intact C2C12 myotubes inhibited insulin-induced GLUT4 recycling without dampening Akt phosphorylation. We found that the peroxisome proliferator-activated receptor ␥ agonist troglitazone prevented the palmitate-induced sortilin reduction and also ameliorated insulin-responsive GLUT4 recycling without altering the palmitate-evoked insults on signaling cascades; neither highly phosphorylated PKC states nor impaired insulin-responsive Akt phosphorylation was affected. Taken together, our data provide novel insights into the pathogenesis of PKC-dependent insulin resistance with respect to insulin-responsive GLUT4 translocation, which could occur not only through defects of insulin signaling but also via a reduction of sortilin, which directly controls trafficking/sorting of GLUT4 in skeletal muscle cells. In addition, our data suggest the insulin-sensitizing action of peroxisome proliferator-activated receptor ␥ agonists to be at least partially mediated through the restoration of proper GLUT4 trafficking/sorting events governed by sortilin.Skeletal muscle cells as well as adipocytes exhibit the highest levels of insulin-stimulated glucose uptake, which is achieved by translocation of the insulin-responsive glucose transporter (GLUT4) from intracellular storage compartment(s) to the plasma membrane (1). It has become increasingly apparent that sortilin, a type I transmembrane protein originally identified as a major component of GLUT4-containing vesicles from rat adipocytes (2, 3), plays crucial roles in the development of the insulin-responsive GLUT4 translocation system not only in adipocytes (4, 5) but also in skeletal muscle cells (6). Evidence available thus far indicates sortilin to be directly involved in the biogenesis of insulin-responsive GLUT4 storage vesicles by regulating sorting events of GLUT4 protein between the transGolgi network and endosomes (4, 5, 7), and experimental suppression of sortilin in adipocytes has been shown to inhibit insulin-responsive GLUT4 translocation (4).Intriguingly, a recent report demonstrated sortilin expression to be significantly reduce...

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“…Several recent reports have supported a role for PKCy and c-Rel in survival via induction of Bcl-X L [30][31][32]. Thus, c-Rel may also play a role in regulating peripheral tolerance by controlling survival versus elimination of potentially self-reactive cells.…”

Section: The Induction Of Anergy Is Not a Consequence Of Impaired Surmentioning

confidence: 99%

“…It has recently been shown that signaling through PKCy leads to the induction of Bcl-X L [30,31] and that this upregulation of Bcl-X L is dependent on c-Rel but is independent of p50 [32]. Furthermore, overexpression of Bcl-X L prevents the induction of tolerance in several transplantation models [33,34].…”

Section: Bcl-x L Does Not Restore T-cell Functionmentioning

confidence: 99%

c‐Rel phenocopies PKCθ but not Bcl‐10 in regulating CD8⁺ T‐cell activation versus tolerance

Deenick

Chapatte

et al. 2010

Eur J Immunol

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Elucidating the signaling events that promote T-cell tolerance versus activation provides important insights for manipulating immunity in vivo. Previous studies have suggested that the absence of PKCh results in the induction of anergy and that the balance between the induction of the transcription factors NFAT, AP1 and NF-jB plays a key role in determining whether T-cell anergy or activation is induced. Here, we examine whether Bcl-10 and specific family members of NF-jB act downstream of PKCh to alter CD8 1 T-cell activation and/or anergy. We showed that T cells from mice deficient in c-Rel but not NF-jB1 (p50) have increased susceptibility to the induction of anergy, similar to T cells from PKCh-deficient mice. Surprisingly T cells from Bcl-10-deficient mice showed a strikingly different phenotype to the PKCh-deficient T cells, with a severe block in TCR-mediated activation. Furthermore, we have also shown that survival signals downstream of NF-jB, are uncoupled from signals that mediate T-cell anergy. These results suggest that c-Rel plays a critical role downstream of PKCh in controlling CD81 T-cell anergy induction.Key words: Anergy . CD8 1 T cells . NF-kB pathway . Tolerance IntroductionUnderstanding the signals that lead to T-cell tolerance versus activation has the potential to be clinically applicable for treatment of autoimmune diseases and promoting anti-tumor responses. Events associated with the induction of T-cell tolerance versus activation are thought to be determined during T-cell interactions with DC. Recognition of Ag together with costimulatory and proinflammatory signals are believed to elicit optimal T-cell activation.Although recent work has identified several molecules that are involved in influencing the anergic state [1,2], it remains unclear how different molecules are connected and integrated by the T cell to induce tolerance or activation. The serine/threonine Eur. J. Immunol. 2010. 40: 867-877 DOI 10.1002 Leukocyte signaling 867 kinase PKCy lies downstream of the TCR and is involved in the activation of NF-kB, AP-1 and NFAT [3][4][5]. Costimulatory signals through CD28 enhance both the recruitment of PKCy to the immunological synapse and its activation [6][7][8][9][10]. Furthermore, studies from several groups support a central role for PKCy in controlling T-cell activation versus anergy [11][12][13]. To further delineate a molecular pathway that is important for the induction of T-cell anergy versus activation, we wanted to examine the role of molecules downstream of PKCy. PKCy activates NF-kB via the CARMA/Bcl-10/MALT complex [14]. Like PKCy À/À T cells [3,4], the T lymphocytes from mice deficient in any of these three molecules show decreased NF-kB activation and have defects in activation and proliferation. The NF-kB family is composed of five members: c-Rel, RelA, RelB, NF-kB1 (p50/p105) and NF-kB2 (p52/p100). Some functions are unique to specific members of this family; for example, RelA deficiency is embryonic lethal due to apoptosis of fetal hepatocytes [15,16]. Significan...

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Protein Kinase C-θ-Mediated Signals Enhance CD4+ T Cell Survival by Up-Regulating Bcl-xL

Cited by 65 publications

References 44 publications

Protein Kinase C-θ Is Required for NK Cell Activation and In Vivo Control of Tumor Progression

Protein Kinase C-θ Is Required for NK Cell Activation and In Vivo Control of Tumor Progression

Palmitate-induced Down-regulation of Sortilin and Impaired GLUT4 Trafficking in C2C12 Myotubes

c‐Rel phenocopies PKCθ but not Bcl‐10 in regulating CD8⁺ T‐cell activation versus tolerance

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Protein Kinase C-θ-Mediated Signals Enhance CD4+ T Cell Survival by Up-Regulating Bcl-xL

Cited by 65 publications

References 44 publications

Protein Kinase C-θ Is Required for NK Cell Activation and In Vivo Control of Tumor Progression

Protein Kinase C-θ Is Required for NK Cell Activation and In Vivo Control of Tumor Progression

Palmitate-induced Down-regulation of Sortilin and Impaired GLUT4 Trafficking in C2C12 Myotubes

c‐Rel phenocopies PKCθ but not Bcl‐10 in regulating CD8+ T‐cell activation versus tolerance

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c‐Rel phenocopies PKCθ but not Bcl‐10 in regulating CD8⁺ T‐cell activation versus tolerance