scholarly journals PRMT5 Promotes Cyclin E1 and Cell Cycle Progression in CD4 Th1 Cells and Correlates With EAE Severity

2021 ◽  
Vol 12 ◽  
Author(s):  
Stephanie A. Amici ◽  
Wissam Osman ◽  
Mireia Guerau-de-Arellano
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Disease Severity ◽  
Cell Cycle Progression ◽  
T Cell Proliferation ◽  
Cycle Progression ◽  
Cyclin E1 ◽  
Relapsing Remitting

Multiple Sclerosis (MS) is a debilitating central nervous system disorder associated with inflammatory T cells. Activation and expansion of inflammatory T cells is thought to be behind MS relapses and influence disease severity. Protein arginine N-methyltransferase 5 (PRMT5) is a T cell activation-induced enzyme that symmetrically dimethylates proteins and promotes T cell proliferation. However, the mechanism behind PRMT5-mediated control of T cell proliferation and whether PRMT5 contributes to diseases severity is unclear. Here, we evaluated the role of PRMT5 on cyclin/cdk pairs and cell cycle progression, as well as PRMT5’s link to disease severity in an animal model of relapsing-remitting MS. Treatment of T helper 1 (mTh1) cells with the selective PRMT5 inhibitor, HLCL65, arrested activation-induced T cell proliferation at the G1 stage of the cell cycle, suggesting PRMT5 promotes cell cycle progression in CD4+ T cells. The Cyclin E1/Cdk2 pair promoting G1/S progression was also decreased after PRMT5 inhibition, as was the phosphorylation of retinoblastoma. In the SJL mouse relapsing-remitting model of MS, the highest PRMT5 expression in central nervous system-infiltrating cells corresponded to peak and relapse timepoints. PRMT5 expression also positively correlated with increasing CD4 Th cell composition, disease severity and Cyclin E1 expression. These data indicate that PRMT5 promotes G1/S cell cycle progression and suggest that this effect influences disease severity and/or progression in the animal model of MS. Modulating PRMT5 levels may be useful for controlling T cell expansion in T cell-mediated diseases including MS.

scholarly journals Inhibition of  T Cell Proliferation by Macrophage Tryptophan Catabolism

1999 ◽  
Vol 189 (9) ◽  
pp. 1363-1372 ◽  
Author(s):  
David H. Munn ◽  
Ebrahim Shafizadeh ◽  
John T. Attwood ◽  
Igor Bondarev ◽  
Achal Pashine ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cell Cycle Progression ◽  
Antigen Presenting Cells ◽  
T Cell Proliferation ◽  
Cycle Progression ◽  
Tryptophan Catabolism ◽  
Antigen Presenting

We have recently shown that expression of the enzyme indoleamine 2,3-dioxygenase (IDO) during murine pregnancy is required to prevent rejection of the allogeneic fetus by maternal T cells. In addition to their role in pregnancy, IDO-expressing cells are widely distributed in primary and secondary lymphoid organs. Here we show that monocytes that have differentiated under the influence of macrophage colony-stimulating factor acquire the ability to suppress T cell proliferation in vitro via rapid and selective degradation of tryptophan by IDO. IDO was induced in macrophages by a synergistic combination of the T cell–derived signals IFN-γ and CD40-ligand. Inhibition of IDO with the 1-methyl analogue of tryptophan prevented macrophage-mediated suppression. Purified T cells activated under tryptophan-deficient conditions were able to synthesize protein, enter the cell cycle, and progress normally through the initial stages of G1, including upregulation of IL-2 receptor and synthesis of IL-2. However, in the absence of tryptophan, cell cycle progression halted at a mid-G1 arrest point. Restoration of tryptophan to arrested cells was not sufficient to allow further cell cycle progression nor was costimulation via CD28. T cells could exit the arrested state only if a second round of T cell receptor signaling was provided in the presence of tryptophan. These data reveal a novel mechanism by which antigen-presenting cells can regulate T cell activation via tryptophan catabolism. We speculate that expression of IDO by certain antigen presenting cells in vivo allows them to suppress unwanted T cell responses.

scholarly journals Epigallocatechin-3-Gallate Directly Suppresses T Cell Proliferation through Impaired IL-2 Utilization and Cell Cycle Progression

2010 ◽  
Vol 140 (8) ◽  
pp. 1509-1515 ◽  
Author(s):  
Munkyong Pae ◽  
Zhihong Ren ◽  
Mohsen Meydani ◽  
Fu Shang ◽  
Simin Nikbin Meydani ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
T Cell ◽  
Cell Cycle Progression ◽  
T Cell Proliferation ◽  
Cycle Progression

scholarly journals K48-linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Zhenyue Hao ◽  
Yi Sheng ◽  
Gordon S. Duncan ◽  
Wanda Y. Li ◽  
Carmen Dominguez ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
T Cell ◽  
Cell Cycle Progression ◽  
E3 Ligase ◽  
T Cell Proliferation ◽  
Cycle Progression

PD-1 Signals Inhibit Cell Cycle Progression by Mediating Upregulation of Both KIP and INK Family of Cdk Inhibitors

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 585-585
Author(s):  
Julia Brown ◽  
Nikolaos Patsoukis ◽  
Vassiliki A Boussiotis
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Cdk Inhibitors ◽  
Cycle Progression ◽  
Smad3 Phosphorylation ◽  
Cells Cultured

Abstract Abstract 585 The PD-1 pathway plays a critical role in the inhibition of T cell activation and the maintenance of T cell tolerance. PD-1 is expressed on activated T cells and limits T cell clonal expansion and effector function upon engagement with its ligands PD-L1 and PD-L2. PD-1 signals are vital for inhibition of autoimmunity whereas PD-1 ligation by PD-L1 and PD-L2 expressed on malignant cells has a detrimental effect on tumor-specific immunity. Furthermore, PD-1 signals result in T cell exhaustion in several chronic viral infections. The mechanism via which PD-1 signals mediate inhibition of T cell expansion is currently poorly understood. Here, we sought to determine the effects of PD-1 signals on mechanistic regulation of cell cycle progression mediated via TCR/CD3 and CD28 in primary human CD4+ T cells using anti-CD3/CD28 with or without agonist anti-PD-1 mAb conjugated to magnetic beads. Cell cycle analysis by ethynyl-deoxyuridine incorporation revealed that PD-1 induced blockade of cell cycle progression at the early G1 phase. To determine the molecular mechanisms underlying the blocked cell cycle progression we examined the expression and activation of cyclins and cdks and the regulation of cdk inhibitors that counterbalance the enzymatic activation of cyclin/cdk holoenzyme complexes. Our studies revealed that PD-1 mediated signals inhibited upregulation of Skp2, the SCF ubiquitin ligase that leads p27kip1 cdk inhibitor to ubiquitin-dependent degradation, and resulted in accumulation of p27kip1. Expression of cyclin E that is induced at the G1/S phase transition, and cyclin A that is synthesized during the S phase of the cell cycle, was dramatically reduced in the presence of PD-1 signaling. Strikingly, although expression of cdk4 and cdk2 was comparable between cells cultured in the presence or in the absence of PD-1, cdk2 enzymatic activation was significantly reduced in the presence of PD-1 signaling. Smad3 is a novel critical cdk substrate. Maximum cdk-mediated Smad3 phosphorylation occurs at the G1/S phase junction and requires activation of cdk2. Phosphorylation by cdk antagonizes TGF-β-induced transcriptional activity and antiproliferative function of Smad3 whereas impaired phosphorylation on the cdk-specific sites renders Smad3 more effective in executing its antiproliferative function. Based on those findings, we examined the effects of PD-1 signaling on Smad3 phosphorylation on cdk-specific and TGF-β-specific sites using site-specific phospho-Smad3 antibodies. Compared to anti-CD3/CD28 alone, culture in the presence of PD-1 induced impaired cdk2 activity, reduced levels of Smad3 phosphorylation on the cdk-specific sites and increased Smad3 phophorylation on the TGF-b-specific site. To determine whether the differential phosphorylation of Smad3 might differentially regulate Smad3 transcriptional activity in CD4+ T cells cultured in the presence versus the absence of PD-1, we examined expression of the INK family cdk4/6 inhibitor p15, a known downstream transcriptional target of Smad3. Expression of p15 was upregulated in CD4+ T cells cultured in the presence of PD-1 but not in cells cultured in the presence of CD3/CD28-coated beads alone. These results indicate that PD-1 signals inhibit cell cycle progression by mediating upregulation of both KIP and INK family of cdk inhibitors and Smad3 is a critical component of this mechanism, regulating blockade at the early G1 phase. Disclosures: No relevant conflicts of interest to declare.

Regulation of the rate of cell cycle progression in quiescent cytolytic T cells by T cell growth factor: Analysis by flow microfluorometry

1984 ◽  
Vol 121 (1) ◽  
pp. 159-166 ◽  
Author(s):  
Rafick P. Sekaly ◽  
H. Robson MacDonald ◽  
Markus Nabholz ◽  
Kendall A. Smith ◽  
Jean-Charles Cerottini
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
Factor Analysis ◽  
T Cell ◽  
Growth Factor ◽  
Cell Growth ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Flow Microfluorometry ◽  
T Cell Growth Factor

Mesenchymal Stem Cells (MSCs) Suppress T Cell Proliferation by a Novel NO-stat5 Dependent Mechanism.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1393-1393
Author(s):  
Kazuya Sato ◽  
Katsutoshi Ozaki ◽  
Iekuni Oh ◽  
Keiko Hatanaka ◽  
Tadashi Nagai ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Molecular Mechanisms ◽  
T Cell Proliferation ◽  
Cd8 Cells ◽  
T Cell Suppression ◽  
Cell Suppression ◽  
Dependent Mechanism

Abstract Mesenchymal stem cells (MSCs) are attractive source for regenerative therapy as they have been shown to be capable of differentiating into adipocytes, chondrocytes, osteoblasts, myocytes, cardiomyocytes, and neural precursors. MSCs have also been shown to suppress T cell proliferation in vitro and were reported to be effective as a treatment for acute graft-versus-host disease (GVHD) but the underlying molecular mechanisms for T cell suppression are uncertain. So far, TGF-β, HGF, and PGE2 were shown to be candidates as molecules causing the suppression. To address the molecular mechanisms, we used primary mouse MSCs derived from bone marrow cells and CFSE (carboxyfluorescein diacetate succinimidyl ester) or thymidine uptake for T cell proliferation assay. Co-culture of MSCs inhibited T cell proliferation induced by PMA plus Ionomycin, suggesting that TCR and signaling molecules interacting with TCR such as Lck and ZAP70 are not involved and that downstream signals of PMA plus Ionomycin are essential for the suppression by MSCs. The proliferation of either purified CD4 or CD8 cells induced by PMA plus Ionomycin was also inhibited by co-culture with MSCs, indicating MSCs suppression is active on both CD4 and CD8 cells. Stat5 phosphorylation in activated T cells was suppressed by co-culture with MSCs. Induction of cell-cycle promoting proteins such as CDK6, Cyclin D2, and Cyclin E by mitogenic stimulation were inhibited and suppression of a cell-cycle inhibitor, Kip1, was abolished. A previous report showed that T cells from stat5 deficient mice failed to induce cell-cycle promoting proteins and were not be able to proliferate on the stimulation through TCR. It was also reported that Nitric Oxide (NO) suppressed stat5 phosphorylation. Taken together with these reports, we hypothesized that NO is another candidate for the cause of suppression. In fact, NO synthase inhibitor (N-nitro-L-arginine methyl ester) recovered T cell proliferation from the suppression by MSCs in a dose-dependent manner. The amount of NO production and the strength of T cell suppression were parallel and dependent on the number of MSCs. MSCs blocked production of IFNγ but induction of T cell activation markers such as CD25 and CD69 and production of IL-2 were unaffected as reported. Our data suggest that MSCs block stat5 phosphorylation by production of NO, resulting in that T cells can neither proliferate nor produce high level of IFNγ. Here we demonstrate a new critical NO-stat5 dependent mechanism for T cell suppression by MSCs.

A Novel p27kip1-Smad3 Regulated Pathway Is Involved in Induction of T Cell Tolerance.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 867-867
Author(s):  
Lequn Li ◽  
Yoshiko Iwamoto ◽  
Alla Berezovskaya ◽  
Vassiliki A. Boussiotis
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
Cell Cycle Progression ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
Wild Type ◽  
Cycle Progression ◽  
Induction Of Tolerance

Abstract Induction and maintenance of peripheral tolerance is essential for homeostasis of the immune system. In vivo studies demonstrate the significance of tolerance induction in preventing autoimmunity, graft rejection and GVHD. Upregulation of the cyclin-dependent kinase inhhibitor, p27, correlates with induction of T cell tolerance in vitro and in vivo. p27 interacts with cdk2, cdc2, grb2, and Rho family GTPases. Extensive studies support an essential role of cdks, particularly cdk2, in cell cycle re-entry. Cdk2 promotes cell cycle progression in part by phosphorylating Rb and related pocket proteins thereby reversing their ability to sequester E2F transcription factors. Recent work indicates that cdk2 phosphorylates Smad2 and Smad3. Smad3 inhibits progression from G1 to S phase, and impaired phosphorylation on the cdk-specific sites renders it more effective in executing this function. In contrast, cdk-mediated phosphorylation of Smad3 reduces Smad3 transcriptional activity and antiproliferative function. In spite the strong correlation between p27 expression level and T cell tolerance, it remains unclear whether p27 has a causative role in induction of tolerance. Here, we examined the role of p27 during induction of tolerance of naïve T cells in vivo, using RAG2 deficient, DO11.10 TCR-transgenic T cells that lack the cyclin-cdk-binding domain of p27 (p27Δ) thereby disrupting only the interactions of p27 with cyclin-cdk complexes. We adoptively transferred CD4+ T cells from RAG2−/−DO11.10 TCR-transgenic mice (DO11.10) or RAG2−/−DO11.10 TCR-transgenic p27Δ mice (DO11.10/p27Δ) into syngeneic wild-type recipients and compared the development of immune responses to immunogenic or tolerizing stimulus in vivo. Following exposure to immunogenic or tolerizing stimulus, DO11.10 and DO11.10/p27Δ CD4+ T cells underwent equal numbers of divisions in vivo, and both cell types exhibited reduced number of divisions in response to tolerizing stimulus. Strikingly, only wild-type DO11.10 TCR-transgenic T cells were tolerized as determined by impaired cyclin E activation, proliferation, and IL-2 production upon antigen-specific rechallenge. Compared to primed wild-type DO11.10 cells, tolerized wild-type DO11.10 cells exhibited impaired cdk2 and cdc2 activity, reduced levels of Smad3 phosphorylation on cdk-specific sites, and increased Smad3-transactivation leading to upregulation of the cdk4/6-specific cdk inhibitor p15. In contrast, after either priming or tolerizing stimulus, DO11.10/p27Δ cells exhibited comparable cdk2 and cdc2 activity, cdk-mediated phosphorylation of Smad3, low-level Smad3 transactivation, and no upregulation of p15. Furthermore, knockdown of Smad3 by expression of Smad3 shRNA in wild-type DO11.10 T cells recapitulated the functional and molecular findings observed in DO11.10/p27Δ cells, preventing induction of tolerance and upregulation of p15, and resulting in production of IL-2 and cell cycle progression. In contrast, expression of Smad3 mutant resistant to cdk-mediated phosphorylation in DO11.10/p27Δ cells recapitulated the molecular and functional effects of tolerance and resulted in inhibition of IL-2 production, upregulation of p15 and blockade of cell cycle progression. These results show that p27 plays a causative role in the induction of tolerance of naïve T cells and Smad3 is a critical component of a pathway downstream of p27 regulating the induction of tolerance in vivo.

Restoration of microRNA-212 causes a G0/G1 cell cycle arrest and apoptosis in adult T-cell leukemia/lymphoma cells by repressing CCND3 expression

2016 ◽  
Vol 65 (1) ◽  
pp. 82-87 ◽  
Author(s):  
Haihao Wang ◽  
Qiannan Guo ◽  
Peiwen Yang ◽  
Guoxian Long
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
T Cell ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Cyclin D3 ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cycle Progression ◽  
Adult T Cell Leukemia

Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive T-cell malignancy. This study was designed to explore the expression and functional significance of microRNA (miR)-212 in ATL. The expression of miR-212 in human ATL tissues and cell lines were investigated. Gain-of-function experiments were carried out to determine the roles of miR-212 in cell proliferation, tumorigenesis, cell cycle progression, and apoptosis. We also identified and functionally characterized the target genes of miR-212 in ATL cells. Compared with normal lymph node biopsies, lymphoma samples from ATL patients displayed underexpression of miR-212 (p=0.0032). Consistently, miR-212 was downregulated in human ATL cell lines, compared with normal T lymphocytes. Restoration of miR-212 significantly (p<0.05) inhibited ATL cell proliferation and tumorigenesis in mice. Overexpression of miR-212 led to an accumulation of G0/G1-phase cells and a concomitant reduction of S-phase cells. Moreover, enforced expression of miR-212-induced significant apoptosis in ATL cells. CCND3, which encodes a cell cycle regulator cyclin D3, was identified as a direct target of miR-212 in ATL cells. Rescue experiments with a miR-212-resistant variant of CCND3 demonstrated that overexpression of CCND3 restored cell-cycle progression and attenuated apoptotic response in miR-212-overexpressing ATL cells. Taken together, miR-212 exerts growth-suppressive effects in ATL cells largely by targeting CCND3 and may have therapeutic potential in ATL.

Imatinib Mesylate Disrupts Cell Cycle Progression, Modifies the Nucleoskeleton and Suppresses Activation-Induced Transcription in Human T Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2914-2914
Author(s):  
Allan Dietz ◽  
William B. Johnson ◽  
Gaylord J. Knutson ◽  
Peggy A. Bulur ◽  
Bertie Schulenberg ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
Imatinib Mesylate ◽  
T Cell Activation ◽  
Cell Cycle Progression ◽  
Cell Activation ◽  
Structural Changes ◽  
Activated T Cells ◽  
Cycle Progression

Abstract Imatinib mesylate (imatinib, Gleevec®, Novartis, Basel, Switzerland) inhibits T cells in vitro and in vivo (Dietz et al., Blood104: 1094–1099, 2004; Cwynarski et al., Leukemia18: 1332–1339, 2004). The drug blocks T cell cycle progression rather uniquely as it neither inhibits expression of CD69, an early marker of T cell activation, nor induces apoptosis. To characterize the molecular effects of imatinib leading to this mode of T-cell inhibition, we measured the changes in transcriptome (by Affymetrix U133 chips), proteome and phosphoproteome (by Western blotting, differential phosphoprotein expression and mass spectrometry). We found that phytohemagglutinin activated T cells pre-treated with imatinib had reduced expression of 983 transcripts and increased expression of 271 transcripts when compared to untreated PHA activated T cells by the factor of 1.5 or more (p&lt;0.05). Among the prominently down-regulated transcripts were granzyme B, CTLA-4 and IL-2-receptor α-chain (CD25), all characteristic of activated T cells, as well as cyclins D2 and D3 and cyclin-dependent kinases 3, 4 and 7, the molecules regulating cell cycle progression. Among the up-regulated transcripts were Kruppel-like transcription factors 2 and 7, and p27, a finding compatible with the observed cell cycle inhibition. Furthermore, we selected and identified 30 proteins from 2-D gels that were up-regulated and/or hyperphosphorylated in imatinib treated activated T cells. Among these were four heterogeneous ribonucleoproteins, three lamins and γ-actin, all components of the nucleoskeleton at the interface of chromatin and inner nuclear membrane and involved in replication and transcription (Herrmann and Foisner, Cell. Mol. Life Sci.60: 1607–1612, 2003; Shumaker et al. Curr. Opinion Cell Biol.15: 358–366, 2003). Thus, imatinib-borne interference with T cell signal transduction affects the nuclear structure indicating for the first time that nucleoskeleton structural changes are associated with T cell activation status.

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