scholarly journals CTLA-4 ligation blocks CD28-dependent T cell activation.

1996 ◽  
Vol 183 (6) ◽  
pp. 2541-2550 ◽  
Author(s):  
T L Walunas ◽  
C Y Bakker ◽  
J A Bluestone
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
Cell Survival ◽  
T Cell Activation ◽  
Cell Cycle Progression ◽  
Cell Activation ◽  
Cell Function ◽  
Receptor Expression ◽  
Negative Regulator ◽  
Cycle Progression

CTLA-4 is a CD28 homologue believed to be a negative regulator of T cell function. However, the mechanism of this downregulatory activity is not well understood. The present study was designed to examine the effect of CTLA-4 ligation on cytokine production, cell survival, and cell cycle progression. The results demonstrate that the primary effect of CTLA-4 ligation is not the induction of apoptosis. Instead, CTLA-4 signaling blocks IL-2 production, IL-2 receptor expression, and cell cycle progression of activated T cells. Moreover, the effect of CTLA-4 signaling was manifested after initial T cell activation. Inhibition of IL-2 receptor expression and cell cycle progression was more pronounced at late (72 h) time points after initial activation. The effects of anti-CTLA-4 mAbs were most apparent in the presence of optimal CD28-mediated costimulation consistent with the finding that CTLA-4 upregulation was CD28-dependent. Finally, the addition of exogenous IL-2 to the cultures restored IL-2 receptor expression and T cell proliferation. These results suggest that CTLA-4 signaling does not regulate cell survival or responsiveness to IL-2, but does inhibit CD28-dependent IL-2 production.

cAMP inhibits both Ras and Rap1 activation in primary human T lymphocytes, but only Ras inhibition correlates with blockade of cell cycle progression

Blood ◽  
2003 ◽  
Vol 101 (3) ◽  
pp. 998-1006 ◽  
Author(s):  
Thomas Grader-Beck ◽  
Andre A. F. L. van Puijenbroek ◽  
Lee M. Nadler ◽  
Vassiliki A. Boussiotis
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Phorbol Ester ◽  
Cell Cycle Progression ◽  
Cell Activation ◽  
Cytokine Production ◽  
Cycle Progression ◽  
Rap1 Activation

Abstract Cyclic adenosine monophosphate (cAMP) is a negative regulator of T-cell activation. However, the effects of cAMP on signaling pathways that regulate cytokine production and cell cycle progression remain unclear. Here, using primary human T lymphocytes in which endogenous cAMP was increased by the use of forskolin and 3-isobutyl-1-methylxanthine (IBMX), we show that increase of cAMP resulted in inhibition of T-cell receptor (TCR)/CD3 plus CD28–mediated T-cell activation and cytokine production and blockade of cell cycle progression at the G1 phase. Increase of cAMP inhibited Ras activation and phosphorylation of mitogen-induced extracellular kinase (MEK) downstream targets extracellular signal–related kinase 1/2 (ERK1/2) and phosphatidylinositol-3-kinase (PI3K) downstream target protein kinase B (PKB; c-Akt). These functional and biochemical events were secondary to the impaired activation of ZAP-70 and phosphorylation of LAT and did not occur when cells were stimulated with phorbol ester, which bypasses the TCR proximal signaling events and activates Ras. Increase of cAMP also inhibited activation of Rap1 mediated by TCR/CD3 plus CD28. Importantly, inhibition of Rap1 activation by cAMP was also observed when cells were stimulated with phorbol ester, although under these conditions Ras was activated and cells progressed into the cell cycle. Thus, TCR plus CD28–mediated activation of ERK1/2 and PKB, cytokine production, and cell cycle progression, all of which are inhibited by cAMP, require activation of Ras but not Rap1. These results indicate that signals that regulate cAMP levels after encounter of T cells by antigen will likely determine the functional fate toward clonal expansion or repression of primary T-cell responses.

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<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.

scholarly journals Preventive CTLA-4-Ig Treatment Reduces Hepatic Egg Load and Hepatic Fibrosis in Schistosoma mansoni-Infected Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-11
Author(s):  
Martina Sombetzki ◽  
Anne Rabes ◽  
Miriam Bischofsberger ◽  
Franziska Winkelmann ◽  
Nicole Koslowski ◽  
...  
Keyword(s):  
T Cell ◽  
Schistosoma Mansoni ◽  
Hepatic Fibrosis ◽  
T Cell Activation ◽  
Egg Production ◽  
Cell Activation ◽  
Cell Function ◽  
T Cell Response ◽  
Negative Regulator ◽  
Egg Load

Background. Hepatic fibrosis and granuloma formation as a consequence of tissue entrapped eggs produced by female schistosomes characterize the pathology of Schistosoma mansoni infection. We have previously shown that single-sex infection with female schistosomes mitigates hepatic fibrosis after secondary infection. This was associated with an increased expression of cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), known as a negative regulator of T cell activation. Based on these findings, we hypothesized that administration of agonistic CTLA-4-Ig (Belatacept) is capable to prevent and/or treat hepatic fibrosis during schistosomiasis. Methods. Mice were infected with 50 S. mansoni cercariae and CTLA-4-Ig, or appropriated control-Ig was administered for 4 weeks. Preventive treatment started 4 weeks after infection, before onset of egg production, and therapeutic treatment started 8 weeks after infection when hepatic fibrosis was already established. Results. When given early after infection, livers of CTLA-4-Ig-treated mice showed significantly reduced collagen deposition and decreased expression of profibrotic genes in comparison to controls. In addition, administration of CTLA-4-Ig suppressed the inflammatory T cell response in infected mice. If therapy was started at a later time point when fibrogenesis was initiated, CTLA-4-Ig had no impact on hepatic fibrosis. Conclusion. We could demonstrate that an early preventive administration of CTLA-4-Ig suppresses effector T cell function and therefore ameliorates liver fibrosis. CTLA-4-Ig administration after onset of egg production fails to treat hepatic fibrosis.

scholarly journals CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells.

1996 ◽  
Vol 183 (6) ◽  
pp. 2533-2540 ◽  
Author(s):  
M F Krummel ◽  
J P Allison
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Cycle Progression ◽  
Cell Activation ◽  
Apoptotic Cell ◽  
Activated T Cells ◽  
Activated State

While interactions between CD28 and members of the B7 family costimulate and enhance T cell responses, recent evidence indicates that the CD28 homologue CTLA-4 plays a downregulatory role. The mechanism by which this occurs is not clear, but it has been suggested that CTLA-4 terminates ongoing responses of activated T cells, perhaps by induction of apoptosis. Here we demonstrate that CTLA-4 engagement by antibody cross-linking or binding to B7 inhibits proliferation and accumulation of the primary T cell growth factor, IL-2, by cells stimulated with anti-CD3 and anti-CD28. This inhibition is not a result of enhanced cell death. Rather it appears to result from restriction of transition from the G1 to the S phase of the cell cycle. Our observation that upregulation of both the IL-2R alpha chain and the CD69 activation antigen are inhibited by CTLA-4 engagement supplies further evidence that CTLA-4 restricts the progression of T cells to an activated state. Together this data demonstrates that CTLA-4 can regulate T cell activation in the absence of induction of apoptotic cell death.

scholarly journals Yap suppresses T cell function and infiltration in the tumor microenvironment

2019 ◽  
Author(s):  
Eleni Stampouloglou ◽  
Anthony Federico ◽  
Emily Slaby ◽  
Stefano Monti ◽  
Gregory L. Szeto ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Cell Biology ◽  
Cell Activation ◽  
Cell Function ◽  
T Cell Responses ◽  
Negative Regulator ◽  
Cell Responses

ABSTRACTA major challenge for cancer immunotherapy is sustaining T cell activation and recruitment in immunosuppressive solid tumors. Here we report that Yap levels are sharply induced upon activation of CD4+ and CD8+ T cells and that Yap functions as an immunosuppressive factor and inhibitor of effector differentiation. Loss of Yap in T cells results in enhanced T cell activation, differentiation and function, which translates in vivo to an improved ability for T cells to infiltrate and repress tumors. Gene expression analyses of tumor-infiltrating T cells following Yap deletion implicates Yap as a mediator of global T cell responses in the tumor microenvironment and as a key negative regulator of T cell tumor infiltration and patient survival in diverse human cancers. Collectively, our results indicate that Yap plays critical roles in T cell biology, and suggest that inhibiting Yap activity improves T cell responses in cancer.

scholarly journals RNA Sequencing to Explore Dominant Isoform Switch During CCR6+ Memory T Cell Activation

2021 ◽  
Author(s):  
Shanrong Zhao ◽  
Alexander Barron ◽  
Ken Dower
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Rna Sequencing ◽  
T Cell Activation ◽  
Cell Cycle Progression ◽  
Cell Activation ◽  
Cell Function ◽  
Control Cell ◽  
Biological Information ◽  
Rna Seq

Abstract Alternative splicing (AS) is an essential, but under-investigated component of T-cell function during immune responses. Recent developments in RNA sequencing (RNA-seq) technologies, combined with the advent of computational tools, have enabled transcriptome-wide studies of AS at an unprecedented scale and resolution. In this paper, we analysed AS in an RNA-seq dataset previously generated to investigate the expression changes during T-cell maturation and antigen stimulation. Eight genes were identified with their most dominant isoforms switched during T cell activation. Of those, seven genes either directly control cell cycle progression or are oncogenes. We selected CDKN2C, FBXO5, NT5E and NET1 for discussion of the functional importance of AS of these genes. Our case study demonstrates that combining AS and gene expression analyses derives greater biological information and deeper insights from RNA-seq datasets than gene expression analysis alone.

scholarly journals l-arginine availability regulates T-lymphocyte cell-cycle progression

Blood ◽  
2006 ◽  
Vol 109 (4) ◽  
pp. 1568-1573 ◽  
Author(s):  
Paulo C. Rodriguez ◽  
David G. Quiceno ◽  
Augusto C. Ochoa
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
Cell Cycle Progression ◽  
Cell Function ◽  
Suppressor Cells ◽  
Cyclin D3 ◽  
Cycle Progression ◽  
Knock Out ◽  
Arginase I

Abstract l-arginine (l-Arg) plays a central role in several biologic systems including the regulation of T-cell function. l-Arg depletion by myeloid-derived suppressor cells producing arginase I is seen in patients with cancer inducing T-cell anergy. We studied how l-Arg starvation could regulate T-cell–cycle progression. Stimulated T cells cultured in the absence of l-Arg are arrested in the G0-G1phase of the cell cycle. This was associated with an inability of T cells to up-regulate cyclin D3 and cyclin-dependent kinase 4 (cdk4), but not cdk6, resulting in an impaired downstream signaling with a decreased phosphorylation of Rb protein and a low expression and binding of E2F1. Silencing of cyclin D3 reproduced the cell cycle arrest caused by l-Arg starvation. The regulation of cyclin D3 and cdk4 by l-Arg starvation occurs at transcriptional and posttranscriptional levels. Signaling through GCN2 kinase is triggered during amino acid starvation. Experiments demonstrated that T cells from GCN2 knock-out mice did not show a decreased proliferation and were able to up-regulate cyclin D3 when cultured in the absence of l-Arg. These results contribute to the understanding of a central mechanism by which cancer and other diseases characterized by high arginase I production may cause T-cell dysfunction.

Rapamycin Blocks IL-2-Driven T Cell Cycle Progression While Preserving T Cell Survival

2001 ◽  
Vol 27 (3) ◽  
pp. 572-585 ◽  
Author(s):  
Juana Gonzalez ◽  
Tom Harris ◽  
Geoffrey Childs ◽  
Michael B. Prystowsky
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
Cell Survival ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
T Cell Survival
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