PKCδ is involved in signal attenuation in CD3+ T cells

Gruber, Thomas; Barsig, Johannes; Pfeifhofer, Christa; Ghaffari-Tabrizi, Nassim; Tinhofer, Ingeborg; Leitges, Michael; Baier, Gottfried

doi:10.1016/j.imlet.2004.08.011

Cited by 22 publications

(23 citation statements)

References 14 publications

(14 reference statements)

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“…In mast cells, it inhibits Ag-receptor induced degranulation (37). Previous work suggested that PKC␦ plays a role in the negative regulation of IL-2 cytokine production and proliferation in T cells (32). The work presented in this study demonstrates for the first time a role of PKC␦ in the positive regulation of an Ag receptormediated function, that is lytic granule exocytosis, in immune cells.…”

Section: Discussionmentioning

confidence: 53%

“…These kinases are components of general TCR-mediated signaling cascade and are, in addition to the regulation of lytic function, involved in control of the other aspects of T cell function, including activation, proliferation, differentiation, and cytokine production (31). Previous studies (32,33) and our work presented in this study indicate that PKC␦ does not have a major role in positive regulation of these functions. In the present work, we show that PKC␦ is required for Ag receptor-induced granule exocytosis-mediated cytotoxicity in CD8 ϩ T cells.…”

Section: Discussionmentioning

confidence: 55%

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Protein Kinase Cδ Regulates Antigen Receptor-Induced Lytic Granule Polarization in Mouse CD8+ CTL

Jennifer

Monu

Shen

et al. 2007

The Journal of Immunology

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T cell receptor (TCR)‐induced activation of protein kinase C (PKC) has long been known to be critical for regulation of granule exocytosis mediated cytotoxicity in CD8+ T cells. However, the mechanism by which PKC regulates this effector function is not clear. In addition, it is not known which PKC family members are involved in the regulation of this process. By combining the use of pharmacological inhibitors and mice with targeted gene deletions, we showed that Protein Kinase C □elta is required for granule exocytosis mediated lytic function in mouse CD8+T cells. We studied lysosomal/lytic granule movements in CD8+ T cells responding to target cell recognition by confocal microscopy and live imaging and demonstrated that PKC □elta regulates TCR induced lytic granule polarization. In summary, our studies identified Protein Kinase C □elta, a member of the family of diacylglycerol dependent, calcium independent PKC isoforms, as a novel regulator of TCR mediated lytic granule release in mouse CD8+CTL. This work was supported by the NIH grants RO1AI48837 and RO1AI41573 to SV and by NIH, NCI F32CA101449‐02 and Research Advisory Council grant to SR.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 55%

Protein Kinase Cδ Regulates Antigen Receptor-Induced Lytic Granule Polarization in Mouse CD8+ CTL

Jennifer

Monu

Shen

et al. 2007

The Journal of Immunology

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“…In this study, we carefully investigate the crosstalk of PKA-and PKC-derived signals during primary CD3 ϩ T-cell activation using pharmacologic inhibitors and activators of PKA, PDE4, and PKC plus our established panel of PKC knock-out mice. 4,[20][21][22][23]43 Our results reveal a nonredundant physiologic counteraction between the positive PKC isotype and the negative cAMP/PKA signaling pathways in regulating the threshold of T-cell activation. Of importance, multiple inhibitory and activatory systems result in consistent data of the critical roles of PKA and PKC: PKA activation (via both PKA activator, Sp-8-Br-cAMP, and PDE4 inhibitor RP73401/piclamilast) plus PKC inhibition (by PKC gene ablation) augment T-cell immunosuppression as measured in TCR/CD28-induced IL-2 secretion responses of T lymphocytes in vitro.…”

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confidence: 67%

“…In contrast, PKC␤, ⑀, ␦, and had been recently shown by us to be dispensable in T-cell signaling. [20][21][22][23] PKC Ϫ/Ϫ T cells already intrinsically demonstrated reduced IL-2 secretion. 4 Therefore, and for direct comparison of CD3/CD28-induced IL-2 production, the DMSO controls of wild-type (wt) and PKC-deficient T cells were normalized to each other and set as 100%.…”

Section: Figure 2 T-cell Activation In Camp Isomer-and Pde4 Lmwi-trementioning

confidence: 97%

PKCθ and PKA are antagonistic partners in the NF-AT transactivation pathway of primary mouse CD3+ T lymphocytes

Hermann-Kleiter

Thuille

Pfeifhofer

et al. 2006

Blood

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We here investigate the crosstalk of PKC and PKA signaling during primary CD3 ؉ T-lymphocyte activation using pharmacologic inhibitors and activators in combination with our established panel of PKC isotype-deficient mouse T cells in vitro. PKC and PKA inversely affect the CD3/ CD28-induced IL-2 expression, whereas other PKC isotypes are dispensable in this signaling pathway. Gene ablation of PKC selectively results in a profound reduction of IL-2 production; however, complete abrogation of IL-2 production in these PKC ؊/؊ T cells was achieved only by simultaneous coactivation of the cAMP/PKA pathway in CD3 ؉ T cells. Conversely, the reduced IL-2 production in PKC inhibitor-treated T cells can be rescued by inhibition of the cAMP/PKA pathway in wild-type but not in PKC ؊ IntroductionFollowing T-cell receptor (TCR) stimulation, lymphocyte activation threshold is coordinated by a complex interplay of distinct signal transduction pathways. The "fine-tuning" of signaling cascades is considered as a crucial step during T-cell activation in order to result in adequate amplitude of an immune response. The molecular processes that regulate the precise level of the immune activation and their complex interpathway integration are, however, still poorly understood. Among several signaling pathways, protein kinase C (PKC) plays an important role in the cellular activation pathway downstream of the antigen receptor. PKC, in particular, is known to translocate to the immunologic synapse. 1 Once activated, PKC plays a critical role in TCR signaling. 2 This is confirmed by analysis of CD3 ϩ T cells of mice lacking PKC. Ex vivo, PKC-deficient T cells are mostly TCR unresponsive and deficient in the production of interleukin 2 (IL-2) due to an impaired transactivation of NF-B, AP-1, and NF-AT. [3][4][5] In strict contrast, the cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) pathway represents a negative regulatory mechanism that controls IL-2 expression in T cells. cAMP itself has been demonstrated to activate directly a class of cyclic nucleotide ion channels 6,7 as well as the Rap1 guanine exchange factors Epac1 and Epac2. 8 The principle cAMP receptor in lymphoid cells, however, is PKA. 9 cAMP is produced after TCR stimulation in T lymphocytes, suggesting the cAMP-mediated repression of T-cell activation may represent a physiologic negative feedback control mechanism. 10 Suppression of cAMP signaling is thus required for T-cell activation. 11 Among other mechanisms, cAMP inhibition is mediated by de novo transcriptional induction of phosphodiesterases (PDEs) upon T-cell activation. In T cells, PDE4 seems to play a particularly important role. 12,13 Increased PDE4 expression in T cells is associated with increased IL-2 production via its hydrolysis of cAMP. 12 Inversely, PDE4 blockade is shown to augment cAMP levels and thus known to abrogate cytokine secretion and proliferation in T cells through inhibition of NF-B and NF-AT and activation of CREB. 13 Several direct targets of cAMP/PKA signaling have be...

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“…Besides, PKC and PKC are PKC-associated PKCs in T cells, and possibly assist in PKC-mediated signaling (25). In contrast to these PKCs, PKC␦ is reported to serve a negative role in TCR-induced IL-2 cytokine production and T cell proliferation (26). However, the mechanism of this negative regulation is not clear so far.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase C-δ Negatively Regulates T Cell Receptor-induced NF-κB Activation by Inhibiting the Assembly of CARMA1 Signalosome

Liu¹,

Ren²,

Gao

et al. 2012

Journal of Biological Chemistry

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PKCδ is involved in signal attenuation in CD3+ T cells

Cited by 22 publications

References 14 publications

Protein Kinase Cδ Regulates Antigen Receptor-Induced Lytic Granule Polarization in Mouse CD8+ CTL

Protein Kinase Cδ Regulates Antigen Receptor-Induced Lytic Granule Polarization in Mouse CD8+ CTL

PKCθ and PKA are antagonistic partners in the NF-AT transactivation pathway of primary mouse CD3+ T lymphocytes

Protein Kinase C-δ Negatively Regulates T Cell Receptor-induced NF-κB Activation by Inhibiting the Assembly of CARMA1 Signalosome

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