scholarly journals Changes in Chromatin Accessibility Across the GM-CSF Promoter upon T Cell Activation Are Dependent on Nuclear Factor κB Proteins

2003 ◽  
Vol 197 (4) ◽  
pp. 413-423 ◽  
Author(s):  
Adele F. Holloway ◽  
Sudha Rao ◽  
Xinxin Chen ◽  
M. Frances Shannon
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chromatin Remodeling ◽  
T Cell Activation ◽  
Cell Activation ◽  
Proximal Promoter ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Aberrant Expression ◽  
Gm Csf

Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a key cytokine in myelopoiesis and aberrant expression is associated with chronic inflammatory disease and myeloid leukemias. This aberrant expression is often associated with constitutive nuclear factor (NF)-κB activation. To investigate the relationship between NF-κB and GM-CSF transcription in a chromatin context, we analyzed the chromatin structure of the GM-CSF gene in T cells and the role of NF-κB proteins in chromatin remodeling. We show here that chromatin remodeling occurs across a region of the GM-CSF gene between −174 and +24 upon T cell activation, suggesting that remodeling is limited to a single nucleosome encompassing the proximal promoter. Nuclear NF-κB levels appear to play a critical role in this process. In addition, using an immobilized template assay we found that the ATPase component of the SWI/SNF chromatin remodeling complex, brg1, is recruited to the GM-CSF proximal promoter in an NF-κB–dependent manner in vitro. These results suggest that chromatin remodeling across the GM-CSF promoter in T cells is a result of recruitment of SWI/SNF type remodeling complexes by NF-κB proteins binding to the CD28 response region of the promoter.

scholarly journals Hypoxia-induced PD-L1/PD-1 crosstalk impairs T-cell function in sleep apnoea

2017 ◽  
Vol 50 (4) ◽  
pp. 1700833 ◽  
Author(s):  
Carolina Cubillos-Zapata ◽  
Jose Avendaño-Ortiz ◽  
Enrique Hernandez-Jimenez ◽  
Victor Toledano ◽  
Jose Casas-Martin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Intermittent Hypoxia ◽  
Cell Activation ◽  
Cell Function ◽  
Sleep Apnoea ◽  
Orphan Receptor ◽  
Dependent Manner ◽  
Obstructive Sleep

Obstructive sleep apnoea (OSA) is associated with higher cancer incidence, tumour aggressiveness and cancer mortality, as well as greater severity of infections, which have been attributed to an immune deregulation. We studied the expression of programmed cell death (PD)-1 receptor and its ligand (PD-L1) on immune cells from patients with OSA, and its consequences on immune-suppressing activity. We report that PD-L1 was overexpressed on monocytes and PD-1 was overexpressed on CD8+ T-cells in a severity-dependent manner. PD-L1 and PD-1 overexpression were induced in both the human in vitro and murine models of intermittent hypoxia, as well as by hypoxia-inducible factor-1α transfection. PD-L1/PD-1 crosstalk suppressed T-cell proliferation and activation of autologous T-lymphocytes and impaired the cytotoxic activity of CD8+ T-cells. In addition, monocytes from patients with OSA exhibited high levels of retinoic acid related orphan receptor, which might explain the differentiation of myeloid-derived suppressor cells. Intermittent hypoxia upregulated the PD-L1/PD-1 crosstalk in patients with OSA, resulting in a reduction in CD8+ T-cell activation and cytotoxicity, providing biological plausibility to the increased incidence and aggressiveness of cancer and the higher risk of infections described in these patients.

Activation of the granulocyte-macrophage colony-stimulating factor promoter in T cells requires cooperative binding of Elf-1 and AP-1 transcription factors

1994 ◽  
Vol 14 (2) ◽  
pp. 1153-1159
Author(s):  
C Y Wang ◽  
A G Bassuk ◽  
L H Boise ◽  
C B Thompson ◽  
R Bravo ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nuclear Protein ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Transcriptional Induction

The granulocyte-macrophage colony-stimulating factor (GM-CSF) gene has been studied extensively as a model system of transcriptional induction during T-lymphocyte activation. The GM-CSF gene is not expressed in resting peripheral blood T cells but is rapidly induced at the transcriptional level following activation through the cell surface T-cell receptor. A highly conserved 19-bp element located immediately 5' of the human GM-CSF TATA box (bp -34 to -52), herein called purine box 1 (PB1), has been shown to bind a T-cell nuclear protein complex and to be required for transcriptional induction of the GM-CSF gene following T-cell activation. The PB1 sequence motif is highly conserved in both human and murine GM-CSF genes. In this report, we demonstrate that the PB1 element alone confers inducibility on a heterologous promoter following transfection into human Jurkat T cells. In addition, we identify a major PB1 nuclear protein-binding complex that is not present in resting peripheral blood T cells but is rapidly induced following T-cell activation. Sequence analysis revealed that PB1 is composed of adjacent binding sites for Ets and AP-1 transcription factors. In vitro mutagenesis experiments demonstrated that both the Ets and AP-1 sites are required for binding of the inducible PB1 nuclear protein complex and for the transcriptional activity of this element and the GM-CSF promoter in activated T cells. Using antibodies specific for different Ets and AP-1 family members, we demonstrate that the major inducible PB1-binding activity present in activated T-cell nuclear extracts is composed of the Elf-1, c-Fos, and JunB transcription factors. Taken together, these results suggest that cooperative interactions between specific Ets and AP-1 family members are important in regulating inducible gene expression following T-cell activation.

scholarly journals Human T cell activation. IV. T cell activation and proliferation via the early activation antigen EA 1.

1989 ◽  
Vol 169 (3) ◽  
pp. 677-689 ◽  
Author(s):  
S Nakamura ◽  
S S Sung ◽  
J M Bjorndahl ◽  
S M Fu
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Early Activation ◽  
Human T Cell ◽  
Accessory Cells ◽  
Activation Antigen

A new mAb G38 was generated against purified EA 1, an early activation antigen. In immunoprecipitation, it was reactive with the same complex precipitated by the initial anti-EA 1 mAb P8. mAb G38 augmented PMA-induced proliferation of PBMC. It was shown to be mitogenic for purified T cells in collaboration with PMA in a dose-dependent manner. This effect was independent of monocytes and other accessory cells. mAb G38 augmented PMA-induced IL-2-R expression. In conjunction with PMA, it induced IL-2 synthesis and secretion. Its effects on IL-2-R and IL-2 expression were documented at both protein and mRNA levels. Both anti-EA 1 mAbs did not induce Ca2+ influx by themselves in PMA-treated T cells. However, the addition of second anti-mouse Ig antibodies induced readily detectable increases in [Ca2+]i. Ca2+-mediated pathways may be utilized as the transduction signal mechanisms. mAb Leu-23 was shown to be reactive with EA 1. mAb Leu-23 was also mitogenic for T cells in the presence of PMA. These findings provide evidence for a functional role for EA 1 in T cell activation and proliferation.

scholarly journals NSOM/QD-Based Visualization of GM1 Serving as Platforms for TCR/CD3 Mediated T-Cell Activation

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Liyun Zhong ◽  
Zhun Zhang ◽  
Xiaoxu Lu ◽  
Shengde Liu ◽  
Crystal Y. Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Imaging System ◽  
Near Field ◽  
Cell Receptor ◽  
Dependent Manner ◽  
Receptor Complexes ◽  
Before And After

Direct molecular imaging of nanoscale relationship between T-cell receptor complexes (TCR/CD3) and gangliosidosis GM1 before and after T-cell activation has not been reported. In this study, we made use of our expertise of near-field scanning optical microscopy(NSOM)/immune-labeling quantum dots- (QD-)based dual-color imaging system to visualize nanoscale profiles for distribution and organization of TCR/CD3, GM1, as well as their nanospatial relationship and their correlation with PKCθsignaling cascade during T-cell activation. Interestingly, after anti-CD3/anti-CD28 Ab co-stimulation, both TCR/CD3 and GM1 were clustered to form nanodomains; moreover, all of TCR/CD3 nanodomains were colocalized with GM1 nanodomains, indicating that the formation of GM1 nanodomains was greatly correlated with TCR/CD3 mediated signaling. Specially, while T-cells were pretreated with PKCθsignaling inhibitor rottlerin to suppress IL-2 cytokine production, no visible TCR/CD3 nanodomains appeared while a lot of GM1 nanodomains were still observed. However, while T-cells are pretreated with PKCαβsignaling inhibitor GÖ6976 to suppress calcium-dependent manner, all of TCR/CD3 nanodomains were still colocalized with GM1 nanodomains. These findings possibly support the notion that the formation of GM1 nanodomains indeed serves as platforms for the recruitment of TCR/CD3 nanodomains, and TCR/CD3 nanodomains are required for PKCθsignaling cascades and T-cell activation

scholarly journals Mechanosensing through YAP controls T cell activation and metabolism

2020 ◽  
Vol 217 (8) ◽  
Author(s):  
Kevin P. Meng ◽  
Fatemeh S. Majedi ◽  
Timothy J. Thauland ◽  
Manish J. Butte
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Viral Infections ◽  
Autoimmune Diabetes ◽  
Tissue Mechanics ◽  
Effector T Cells ◽  
Metabolic Reprogramming ◽  
Dependent Manner

Upon immunogenic challenge, lymph nodes become mechanically stiff as immune cells activate and proliferate within their encapsulated environments, and with resolution, they reestablish a soft baseline state. Here we show that sensing these mechanical changes in the microenvironment requires the mechanosensor YAP. YAP is induced upon activation and suppresses metabolic reprogramming of effector T cells. Unlike in other cell types in which YAP promotes proliferation, YAP in T cells suppresses proliferation in a stiffness-dependent manner by directly restricting the translocation of NFAT1 into the nucleus. YAP slows T cell responses in systemic viral infections and retards effector T cells in autoimmune diabetes. Our work reveals a paradigm whereby tissue mechanics fine-tune adaptive immune responses in health and disease.

A phase I trial of combination immunotherapy with CTLA-4 blockade and GM-CSF in hormone-refractory prostate cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2508-2508 ◽  
Author(s):  
L. Fong ◽  
B. Kavanagh ◽  
B. I. Rini ◽  
V. Shaw ◽  
V. Weinberg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Response Relationship ◽  
Dose Response Relationship ◽  
Antibody Treatment ◽  
Gm Csf ◽  
Clinical Responses ◽  
Hormone Refractory

2508 Background: CTLA-4 is an costimulatory molecule expressed on activated T cells that delivers an inhibitory signal to these T cells. CTLA-4 blockade with antibody treatment augments T cell responses and anti-tumor immunity in animal models. Clinical trials with anti-CTLA-4 antibody treatment have demonstrated clinical responses in different malignancies including melanoma and hormone-refractory prostate cancer (HRPC). We have also shown that administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) can also induce PSA declines in HRPC patients, presumably through enhancing presentation of endogenous antigens. The current study examines whether combining systemic GM-CSF to CTLA-4 blockade can augment immune and/or clinical responses in HRPC patients. Methods: In a phase I trial of patients with metastatic HRPC, sequential cohorts of 3–6 patients received GM-CSF (sargramostim, Berlex) 250 mg/m2/d SC on days 1–14 of a 28-day cycle with escalating doses (0.5, 1.5 or 3 mg/kg) of ipilimumab (MDX-010), a fully human anti-CTLA antibody (Medarex/BMS), given IV on day 1 of each cycle x 4 cycles. Patients were monitored for toxicity as well as for T cell activation. PSA and radiographic tests were performed at baseline and through therapy to evaluate for clinical response. Results: 18 patients were accrued. Ipilimumab-related dose-limiting toxicity was limited to one patient with grade 3 rash at the 3 mg/kg priming dose level. Seven patients had <50% declines in their serum PSA levels. A dose response relationship was seen between ipilimumab dose and activation of both CD4 and CD8 T cells in the blood. These effects were increased compared to effects seen with ipilimumab treatment alone in prior studies. Interferon-gamma production and lytic activity were also enhanced in circulating antigen-specific CD8+ T cells by the combination. Conclusions: GM-CSF may enhance T cell activation induced by CTLA-4 blockade. With increasing doses of anti-CTLA-4, both CD4 and CD8 T cell activation can be detected in the blood, consistent with a dose-response relationship. Supported by the UCSF Prostate SPORE NIH P50 CA89520. No significant financial relationships to disclose.

Juzentaihoto Exerts Anti-Allergic Effects by Inhibiting Effector T-Cell Activation and Inducing and/or Activating Regulatory T Cells in a Murine Model of Contact Hypersensitivity

2021 ◽  
pp. 1-13
Author(s):  
Atsushi Tsuge ◽  
Sho Yonekura ◽  
Satomi Watanabe ◽  
Yuta Kurosaki ◽  
Shinsuke Hisaka ◽  
...  
Keyword(s):  
T Cells ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Effector T Cells ◽  
Contact Hypersensitivity ◽  
Dependent Manner ◽  
Effector T Cell

<b><i>Background:</i></b> Juzentaihoto (JTT) is a Kampo prescription that has been used clinically for treating skin diseases such as atopic dermatitis in Japan. We have previously studied the anti-allergic effects of JTT on 2,4,6-trinitrochlorobenzene (TNCB)-induced contact hypersensitivity (CHS) in mice and demonstrated that it significantly suppresses ear swelling in a dose-dependent manner. However, the mechanism underlying the anti-allergic actions of JTT is obscure. <b><i>Methods:</i></b> We investigated the mechanism underlying the anti-allergic effects of JTT using a TNCB-induced murine CHS model and adoptive cell transfer experiments. <b><i>Results:</i></b> We showed that the anti-allergic effects of JTT are due to inhibition of effector T-cell activation and induction and/or activation of regulatory T cells. Furthermore, ex vivo experiments confirmed the effect of JTT on the activation of effector T cells and regulatory T cells, as interferon-γ production decreased, whereas interleukin (IL)-10 production increased, in the cultured lymphocytes obtained from 5% TNCB-sensitized mice treated with anti-CD3ε and anti-CD28 monoclonal antibodies. Flow cytometry showed that the CD4<sup>+</sup>CD25<sup>+</sup>Foxp3<sup>+</sup>, CD4<sup>+</sup>CD25<sup>+</sup>Foxp3<sup>−</sup>, and CD8<sup>+</sup>CD122<sup>+</sup> cell population increased after oral administration of JTT. Finally, the anti-allergic effect of JTT by inducing and/or activating regulatory T cells (Tregs) was confirmed to be mediated by IL-10 through in vivo neutralization experiments with anti-IL-10 monoclonal antibodies. <b><i>Conclusion:</i></b> We suggested that JTT exerts anti-allergic effects by regulating the activation of effector T cells and Tregs involved in murine CHS model.

scholarly journals Human T cell activation. I. Monocyte-independent activation and proliferation induced by anti-T3 monoclonal antibodies in the presence of tumor promoter 12-o-tetradecanoyl phorbol-13 acetate.

1985 ◽  
Vol 161 (4) ◽  
pp. 641-656 ◽  
Author(s):  
T Hara ◽  
S M Fu
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Receptor Expression ◽  
T Cell Proliferation ◽  
Dependent Manner ◽  
Human T Cell

Three monoclonal antibodies (mAb), of IgG1, IgG2a, and IgM isotypes, raised against the T3 complex, were used to probe the activation of human T cells. The IgM antibody 235 was not mitogenic for peripheral blood mononuclear cells (PMC). It efficiently blocked the proliferation of PMC induced by T cell mitogens, alloantigens, and soluble antigens. The other two antibodies were mitogenic, and behaved similarly to Leu 4 and OKT3, respectively. In T cell preparations with less than 0.1% monocytes (as assayed by nonspecific esterase staining), all three mAb were not mitogenic. They failed to induce either interleukin 2 (IL-2) receptor expression or IL-2 secretion. Addition of IL-1 failed to collaborate with anti-T3 mAb to induce these T cells to proliferate, but IL-2 enhanced T cell proliferation slightly. Monocyte-depleted T cells, however, proliferated in response to all three anti-T3 mAb, when TPA was added, in a dose-dependent manner. TPA induced a low level of IL-2 receptor expression in monocyte-depleted T cells, without inducing IL-2 secretion. Anti-T3 plus TPA induced a marked enhancement in both quantity and intensity of IL-2 receptor expression. IL-2 secretion was also detected. These results indicate that anti-T3 IgM can deliver an inductive signal despite its blockage of T cell proliferation, and that two signals are necessary and perhaps sufficient to induce human T cell activation and proliferation.

scholarly journals p21ras and calcineurin synergize to regulate the nuclear factor of activated T cells.

1993 ◽  
Vol 178 (5) ◽  
pp. 1517-1522 ◽  
Author(s):  
M Woodrow ◽  
N A Clipstone ◽  
D Cantrell
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Protein Tyrosine Kinase ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Cytosolic Calcium ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Guanine Nucleotide Binding Protein

In T lymphocytes, triggering of the T cell receptor (TCR) induces several signaling cascades which ultimately synergize to induce the activity of the nuclear factor of activated T cells (NFAT), a DNA binding complex critical to the inducibility and T cell specificity of the T cell growth factor interleukin 2. One immediate consequence of T cell activation via the TCR is an increase in cytosolic calcium. Calcium signals are important for NFAT induction, and recent studies have identified calcineurin, a calcium-calmodulin dependent serine-threonine phosphatase, as a prominent component of the calcium signaling pathway in T cells. A second important molecule in TCR signal transduction is the guanine nucleotide binding protein, p21ras, which is coupled to the TCR by a protein tyrosine kinase dependent mechanism. The experiments presented here show that expression by transfection of mutationally activated calcineurin or activated p21ras alone is insufficient for NFAT transactivation. However, coexpression of the activated calcineurin with activated p21ras could mimic TCR signals in NFAT induction. These data identify calcineurin and p21ras as cooperative partners in T cell activation.

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