Regulation of IgD-Receptor Expression on Murine T Cells

Amin, Ashok R.; Swenson, Christina D.; Xue, Bin; Ishida, Yasuo; Nair, Bipin G.; Patel, T. B.; Chused, Thomas M.; Thorbecke, G. J.

doi:10.1006/cimm.1993.1302

Cited by 17 publications

(5 citation statements)

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“…KN-93 and W-7 have been shown previously to inhibit calciumdependent CaM kinase II and calmodulin, respectively, in T cells (34,35). As shown in Fig.…”

Section: Activation-induced Sermentioning

confidence: 95%

A Protein Kinase C-, Ras-, and RSK2-dependent Signal Transduction Pathway Activates the cAMP-responsive Element-binding Protein Transcription Factor following T Cell Receptor Engagement

Muthusamy

Leiden

1998

Journal of Biological Chemistry

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The cAMP-responsive element-binding protein (CREB) transcription factor is required for normal T cell activation following stimulation through the T cell antigen receptor (TCR). CREB is present in resting T cells in an unphosphorylated and inactive state. TCR engagement results in the rapid phosphorylation of CREB on Ser 133 and its concomitant activation. In the studies described in this report, we have investigated the signaling pathway(s) that are responsible for CREB activation in normal T cells. Using pharmacological agonists, we show that protein kinase C (PKC)-, calcium/calmodulin-, and protein kinase A-dependent pathways are each capable of independently eliciting CREB phosphorylation in T cells and thymocytes. Pharmacological inhibitor studies demonstrated that the PKC-mediated signaling pathway is required for TCR-mediated activation of CREB. In contrast, inhibitors of protein kinase A and calmodulin kinases had no effect on CREB phosphorylation following TCR cross-linking. T cells lacking the p56 lck tyrosine kinase failed to phosphorylate CREB in response to TCR engagement. Overexpression of dominant-negative mutant Ras and Raf-1 proteins in Jurkat T cells abolished TCR-mediated CREB phosphorylation, whereas overexpression of the RSK2 serine/threonine kinase significantly potentiated TCR-mediated CREB phosphorylation. Taken together, these experiments are consistent with a model in which TCR engagement leads to the rapid phosphorylation and activation of CREB via a signaling pathway involving the activation of p56 lck , PKC, Ras, Raf-1, MEK, and RSK2. Given the importance of CREB phosphorylation in normal T cell activation, this pathway may be an attractive target for the development of novel immunosuppressive agents. (8, 9). Previous studies have demonstrated that multiple signaling pathways in different cell lineages can mediate the phosphorylation and activation of CREB. These include a protein kinase A (PKA)-dependent pathway that is activated by increased intracellular cAMP (2, 3), a calcium/calmodulin-dependent pathway in which CREB can be phosphorylated by CaM kinases II and IV (10), and a Ras-dependent pathway in which the serine/threonine kinase RSK2 is thought to phosphorylate CREB on Ser 133 (11).Recent studies have demonstrated that transcriptionally active CREB is required for the activation of normal murine T cells following engagement of the T cell antigen receptor (12). Resting T cells contain exclusively unphosphorylated and inactive CREB. TCR cross-linking leads to the rapid and transient phosphorylation of CREB on Ser 133 . More important, transgenic mice expressing a dominant-negative unphosphorylatable form of CREB display a profound T cell proliferative defect characterized by G 1 cell cycle arrest, markedly decreased IL-2 production, and defective transcriptional induction of multiple Fos and Jun proteins (12). These results were consistent with other reports that demonstrated that T and B cell activation results in CREB phosphorylation and increased CREB DNA-binding activity ...

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“…KN-93 and W-7 have been shown previously to inhibit calciumdependent CaM kinase II and calmodulin, respectively, in T cells (34,35). As shown in Fig.…”

Section: Activation-induced Sermentioning

confidence: 95%

A Protein Kinase C-, Ras-, and RSK2-dependent Signal Transduction Pathway Activates the cAMP-responsive Element-binding Protein Transcription Factor following T Cell Receptor Engagement

Muthusamy

Leiden

1998

Journal of Biological Chemistry

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“…Reports focusing on IgDR-related signaling were previously limited. In mice, crosslinking of IgDR might induce signal transduction through the activation of PTK pathways ( Amin et al, 1993 ); total protein expression of IgDR and phosphorylation of Lck were previously shown to be enhanced by IgD in mouse T cells ( Lakshmi et al, 2001 ). Furthermore, the tyrosine kinase Lck plays a crucial role in the maturation of lymphocytes in the thymus and in mature T cell activation and proliferation ( Gascoigne and Palmer, 2011 ; Barrera-Vargas et al, 2014 ; Klammt et al, 2015 ; Vahedi et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

“…However, the expression of Lck was not changed. A previous study showed that HA, which is a tyrosine kinase inhibitor, can block PTK signaling and significantly inhibit the induction of IgDR in murine cells ( Amin et al, 1993 ; Swenson et al, 1993 ). We used the inhibitors HA and A770041 to confirm whether Lck is the key molecular mediator of IgD-induced T cell activation.…”

Section: Discussionmentioning

confidence: 99%

CP-25 Attenuates the Activation of CD4+ T Cells Stimulated with Immunoglobulin D in Human

Chen

et al. 2018

Front. Pharmacol.

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Researchers have shown that the level of immunoglobulin D (IgD) is often elevated in patients with autoimmune diseases. The possible roles of IgD on the function of human T cell activation are still unclear. Paeoniflorin-6′-O-benzene sulfonate (code: CP-25), the chemistry structural modifications of paeoniflorin, was a novel drug of anti-inflammation and immunomodulation. The aims of this study were to determine if human CD4+ T cells could be activated by IgD via the IgD receptor (IgDR)-Lck pathway and whether the novel compound CP-25 could affect the activation of T cells by regulating Lck. Human CD4+ T cells were purified from peripheral blood mononuclear cells using microbeads. T cell viability and proliferation were detected by Cell Counting Kit-8 and CFSE Cell Proliferation Kit. Cytokines secreted by T cells were assessed with the Quantibody Human Inflammation Array. The binding affinity and expression of IgDR on T cells were detected by flow cytometry, and protein expression of IgDR, Lck, and P-Lck were analyzed by western blot. IgD was shown to bind to IgDR on CD4+ T cells in a concentration-dependent manner and stimulate the activation and proliferation of these cells by enhancing phosphorylation of the activating tyrosine residue of Lck (Tyr394). CP-25 inhibited the IgD-stimulated activation and proliferation of CD4+ T cells, as well as the production of inflammatory cytokines; it was thus suggested that this process might be related to the downregulation of Lck (Tyr394) phosphorylation. These results demonstrate that IgD amplifies the activation of CD4+ T cells, which could be mediated by Lck phosphorylation. Further, CP-25, via its ability to modulate Lck, is a novel potential therapeutic agent for the treatment of human autoimmune diseases.

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“…In the first place, both could be the result of a common T cell defect, perhaps in T cell triggering. Up-regulation of IgD-R was previously shown to require tyrosine kinase activity [6] and so does activation of T cells via the TCR [20]. Secondly, it is possible that IgD-R expression itself is needed for acquisition of optimal T cell helper function in antibody production.…”

Section: Discussionmentioning

confidence: 99%

IgD‐receptor up‐regulation on human peripheral blood T cells in response to IgD in vitro or antigen in vivo correlates with the antibody response to influenza vaccination

Swenson

Cherniack²,

Russo

et al. 1996

Eur J Immunol

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Aged individuals (more than 65 years) were classified as antibody (Ab) responders on the basis that they showed increases to more than or = 1:40 in serum Ab titers to all influenza virus strains present in the trivalent influenza vaccine within 4 weeks after immunization. The peripheral blood mononuclear cells (PBMC) from pre-immunization samples of blood taken from seven Ab-responders and seven Ab-nonresponders were examined for their ability to exhibit up-regulation of IgD-receptor (IgD-R) after exposure for 2 h to immobilized cross-linked IgD, as shown by rosetting with IgD-coated ox erythrocytes. The responsiveness to IgD was found to be predictive of the ability to produce Ab responses to viral protein Ag: the IgD-R up-regulation was greater than 5% in all Ab-responders and less than 4% in all the Ab-nonresponders. In addition, there was an excellent correlation between mean Ab titers (to the three viruses in sera collected 4 weeks after immunization) and the percentage of IgD-R+ cells obtained in response to IgD in PBMC from the same individual prior to immunization: p = 0.894. Injection of influenza vaccine itself also induced IgD-R on PBMC in vivo. The percentage of IgD-R+ cells peaked after 24 h, was still detectable above background by day 7 or 14, and returned to pre-injection levels by day 28 in young subjects and aged Ab-responders, but not in Ab-nonresponders. Similarly, purified peripheral blood T cells obtained from aged Ab-responders exhibited IgD-R upon immunization in vivo. These findings suggest that Ag injection causes rapid up-regulation of IgD-R by cross-linking IgD in humans as well as in mice as shown previously. In analogy with results in mice, the present data are consistent with a role for IgD-R+ T cells in the humoral response in man. Proliferative responses to influenza proteins in peripheral blood T cells from vaccinated individuals were found to peak on day 7 and were higher in Ab-responders than in Ab-nonresponders.

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Regulation of IgD-Receptor Expression on Murine T Cells

Cited by 17 publications

References 0 publications

A Protein Kinase C-, Ras-, and RSK2-dependent Signal Transduction Pathway Activates the cAMP-responsive Element-binding Protein Transcription Factor following T Cell Receptor Engagement

A Protein Kinase C-, Ras-, and RSK2-dependent Signal Transduction Pathway Activates the cAMP-responsive Element-binding Protein Transcription Factor following T Cell Receptor Engagement

CP-25 Attenuates the Activation of CD4+ T Cells Stimulated with Immunoglobulin D in Human

IgD‐receptor up‐regulation on human peripheral blood T cells in response to IgD in vitro or antigen in vivo correlates with the antibody response to influenza vaccination

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