Defective IgG2a/2b Class Switching in PKCα−/− Mice

Pfeifhofer, Christa; Gruber, Thomas; Letschka, Thomas; Thuille, Niκolaus; Lutz-Nicoladoni, Christina; Hermann-Kleiter, Natascha; Braun, Ursula; Leitges, Michael; Baier, Gottfried

doi:10.4049/jimmunol.176.10.6004

Cited by 81 publications

(69 citation statements)

References 26 publications

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“…Both PKC 4 and, as very recently observed by us, PKC␣ 43 are shown to IL-2 production of purified naive CD3 ϩ T cells in the presence of the panPKC LMWI inhibitor, which reduces the proliferation (P ϭ .016) and IL-2 secretion (P ϭ .003) significantly. Cells were left unstimulated or were stimulated with anti-CD3 (precoated at a concentration of 10 g mL Ϫ1 ) plus soluble anti-CD28 (1 g mL Ϫ1 ), as indicated, and analysis was done by using standard procedures.…”

Section: Additive Effects Of Pkc and Pka Modulations In Primary Cd3 ؉mentioning

confidence: 55%

“…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.…”

mentioning

confidence: 87%

“…Of importance, however, no such combinatorial effect can be observed when using the PKC␣-deficient T cells. 43 In response to either of the stimuli, neither proliferation nor IL-2 secretion of CD3 ϩ T cells from the PKC␣ Ϫ/Ϫ mice was further reduced in the presence of PDE4 LMWI relative to that of wild-type T cells ( Figure 5C-D). The normalized effects of PDE4 LMWI in percent induction of CD3/CD28-induced proliferation, and IL-2 production of CD3 ϩ wild-type and PKC-or PKC␣-deficient T cells (DMSO control was set as 100% in each genotype for direct comparison purposes), are shown (Table 2).…”

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

confidence: 99%

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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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Section: Additive Effects Of Pkc and Pka Modulations In Primary Cd3 ؉mentioning

confidence: 55%

mentioning

confidence: 87%

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

confidence: 99%

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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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“…Previously, PKC-a was shown to be required for Th1 celldependent IgG2a/2b antibody responses in vivo [41]. Whether the loss of PKC-a expression or inhibition of PKC-a activity would lead to enhanced susceptibility to bacterial infections requires further investigation.…”

Section: Discussionmentioning

confidence: 98%

PKC‐α controls MYD88‐dependent TLR/IL‐1R signaling and cytokine production in mouse and human dendritic cells

et al. 2010

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Conventional PKC (cPKC)-a regulates TRIF-dependent IFN response factor 3 (IRF3)-mediated gene transcription, but its role in MyD88-dependent TLR signaling remains unknown. Herein, we demonstrate that PKC-a is induced by several MyD88-dependent TLR/IL-1R ligands and regulates cytokine expression in human and murine DC. First, inhibition of cPKC activity in human DC by cPKC-specific inhibitors, Gö 6976 or HBDDe, downregulated the production of classical inflammatory/immunomodulatory cytokines induced by TLR2, TLR5 or IL-1R but not by TLR3 stimulation. Similarly, dominant negative PKC-a repressed Pam 3 CSK 4 induced NF-jB-and AP-1-driven promoter activities in TLR2-expressing human embryonic kidney 293 T cells. Dominant negative PKC-a inhibited NF-jB reporter activity mediated by overexpression of MyD88 but not TRIF. Unexpectedly, BM-derived DC from PKC-a À/À mice exhibited decreased TNF-a and IL-12p40 production induced by both MyD88-and TRIF-dependent ligands. Furthermore, PKC-a is coupled to TLR2 signaling proximal to MyD88 since MAPK and IjB kinase-a/b phosphorylations and IjBa degradation were inhibited in PKC-a À/À BM-derived DC. Finally, co-immunoprecipitation assays revealed that PKC-a physically interacts with Pam 3 CSK 4 activated TLR2 in WT but not in MyD88 À/À DC. Collectively this study identifies a species-specific role of PKC-a as a key component that controls MyD88-dependent cytokine gene expression in human and mouse but differentially regulates production of TRIF-dependent cytokines.Key words: MyD88 . PKC . TLR Supporting Information available online Introduction TLR are a family of evolutionary conserved transmembrane proteins that are expressed on numerous cell types including Mf and DC. They function as pathogen recognition receptors, sensing a wide range of invading pathogens including bacteria, fungi and viruses through recognition of PAMP. Engagement of TLR by microbial products triggers the activation of two distinct signaling pathways: the MyD88-dependent and -independent pathways, Ã These authors contributed equally to this work.ÃÃ These authors contributed equally to this work. [4,5]. Recent studies identified several PKC isoforms as key regulators of TLR signaling pathways. PKC serine/threonine kinase family is classified into three groups according to their structure homology and co-factor regulation (conventional PKC (a, bI, bII, and g), novel PKC (d, e, y and Z/L) and atypical PKC (l/i and z)) [6,7]. PKC-e À/À Mf display a major defect in their ability to generate inflammatory mediators in response to LPS and are highly susceptible to Gram-positive and Gram-negative infections [8,9]. PKC-e is also involved in LPS-induced MAPK phosphatase 1 expression in MF and plays a critical role in LPS-induced IL-12p70 and TNF-a production in DC [10,11]. PKC-e À/À and PKC-d À/À MF display an impaired activation of NF-kB and MAPK downstream of TLR2 and TLR4 [8,12]. PKC-d is necessary to induce Stat-1 activation in response to LPS in murine MF [13]. PKC-z is implicated in LPS-induced MAPK and NF-kB...

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“…CD28 signaling through PI3K results in the recruitment of PKCθ to the cSMAC, and then, activation of NF-κB, as well as induction of IL-2 transcription (50). Besides this, PKCα is also necessary for T cell-dependent IFN-γ production, because CD3/CD28 antibodies and MHC alloantigen induced PKCα-deficient T cells were severely impaired in IFN-γ production (51). Similarly to PKC isotypes, CD28 binding Grb2-related adaptor protein 2 (Gads) is also essential for CD28-mediated NF-κB activation, and its binding requires the whole CD28 cytoplasmic domain in addition to the YMNM motif.…”

Section: Intracellular Signals Of Costimulation In T Cell Responsementioning

confidence: 99%

Intracellular Signals of T Cell Costimulation

et al. 2008

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Defective IgG2a/2b Class Switching in PKCα−/− Mice

Cited by 81 publications

References 26 publications

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

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

PKC‐α controls MYD88‐dependent TLR/IL‐1R signaling and cytokine production in mouse and human dendritic cells

Intracellular Signals of T Cell Costimulation

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