scholarly journals Upregulated expression and function of VLA-4 fibronectin receptors on human activated T cells in rheumatoid arthritis.

1991 ◽  
Vol 88 (2) ◽  
pp. 546-552 ◽  
Author(s):  
A Laffón ◽  
R García-Vicuña ◽  
A Humbría ◽  
A A Postigo ◽  
A L Corbí ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Activated T Cells ◽  
And Function

NFATc3 regulates the transcription of genes involved in T-cell activation and angiogenesis

Blood ◽  
2011 ◽  
Vol 118 (3) ◽  
pp. 795-803 ◽  
Author(s):  
Katia Urso ◽  
Arantzazu Alfranca ◽  
Sara Martínez-Martínez ◽  
Amelia Escolano ◽  
Inmaculada Ortega ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Target Genes ◽  
Gene Knockout ◽  
Activated T Cells ◽  
Knock Down ◽  
And Function

Abstract The nuclear factor of activated T cells (NFAT) family of transcription factors plays important roles in many biologic processes, including the development and function of the immune and vascular systems. Cells usually express more than one NFAT member, raising the question of whether NFATs play overlapping roles or if each member has selective functions. Using mRNA knock-down, we show that NFATc3 is specifically required for IL2 and cyclooxygenase-2 (COX2) gene expression in transformed and primary T cells and for T-cell proliferation. We also show that NFATc3 regulates COX2 in endothelial cells, where it is required for COX2, dependent migration and angiogenesis in vivo. These results indicate that individual NFAT members mediate specific functions through the differential regulation of the transcription of target genes. These effects, observed on short-term suppression by mRNA knock-down, are likely to have been masked by compensatory effects in gene-knockout studies.

CD101 Expression and Function in Normal and Rheumatoid Arthritis-affected Human T Cells and Monocytes/Macrophages

2010 ◽  
Vol 38 (3) ◽  
pp. 419-428 ◽  
Author(s):  
DRAGAN V. JOVANOVIC ◽  
LAURENCE BOUMSELL ◽  
ARMAND BENSUSSAN ◽  
XAVIER CHEVALIER ◽  
ARTURO MANCINI ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Regulatory T Cells ◽  
Map Kinase ◽  
Surface Expression ◽  
P38 Map Kinase ◽  
Autoimmune Response ◽  
Human Immune System ◽  
Kinase Activation ◽  
And Function

Objective.It was recently reported that CD101 surface expression discriminates potency among CD4+CD25+ FoxP3+ regulatory T cells in the mouse. We investigated whether CD101 may also have a role in the suppressor function of regulatory T cells in humans given that the latter population may affect the autoimmune response in patients with rheumatoid arthritis (RA).Methods.Sorted T cells and monocyte/macrophage cell populations were analyzed by flow cyto metry using conjugated antibodies specific for cell-surface markers. T cell proliferation assays were conducted by [3H]thymidine incorporation and CD8highcytotoxicity measurements by Cyto-Scan-LDH cytotoxicity assays. ELISA were used to measure cytokines in cell culture supernatants and Western blotting was performed for profiling mitogen-activated protein (MAP) kinase activation using specific antiphospholipid antibodies.Results.CD101 expression coincided with PMA-induced monocyte/leukocyte lineage differentiation. CD8highCD101− T cells exhibited greater cytotoxic activity than CD8highCD101+ T cells, while no difference was observed between CD4CD25highCD101+ and CD4CD25highCD101− Treg inhibitory activity through responder T cells. LPS-induced proinflammatory cytokine production and p38 MAP kinase activation were made possible by ligation of CD101 with an anti-CD101 antibody F(ab’)2fragment.Conclusion.These results suggested a modulatory/coregulatory function of CD101 in the human immune system, in contrast to murine models, in which CD101 surface expression discriminates potency among FoxP3+ regulatory T cells. Cytotoxic CD8highCD101+ T cells were markedly less cytotoxic than CD8highT cells negative for the CD101 antigen and were conspicuously downregulated in patients with RA, suggesting a possible role for CD101 expression and function in the control of certain manifestations of RA pathology.

scholarly journals Revisiting the PD-1 pathway

2020 ◽  
Vol 6 (38) ◽  
pp. eabd2712 ◽  
Author(s):  
Nikolaos Patsoukis ◽  
Qi Wang ◽  
Laura Strauss ◽  
Vassiliki A. Boussiotis
Keyword(s):  
T Cells ◽  
Molecular Targets ◽  
Peripheral Tolerance ◽  
Inhibitory Receptor ◽  
Activated T Cells ◽  
Therapeutic Success ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
And Function ◽  
Blocking Antibodies

Programmed Death-1 (PD-1; CD279) is an inhibitory receptor induced in activated T cells. PD-1 engagement by its ligands, PD-L1 and PD-L2, maintains peripheral tolerance but also compromises anti-tumor immunity. Blocking antibodies against PD-1 or its ligands have revolutionized cancer immunotherapy. However, only a fraction of patients develop durable antitumor responses. Clinical outcomes have reached a plateau without substantial advances by combinatorial approaches. Thus, great interest has recently emerged to investigate, in depth, the mechanisms by which the PD-1 pathway transmits inhibitory signals with the goal to identify molecular targets for improvement of the therapeutic success. These efforts have revealed unpredictable dimensions of the pathway and uncovered novel mechanisms involved in PD-1 and PD-L1 regulation and function. Here, we provide an overview of the recent advances on the mechanistic aspects of the PD-1 pathway and discuss the implications of these new discoveries and the gaps that remain to be filled.

scholarly journals Nuclear factor of activated T cells 2 is required for osteoclast differentiation and function in vitro but not in vivo

2018 ◽  
Vol 119 (11) ◽  
pp. 9334-9345 ◽  
Author(s):  
Jungeun Yu ◽  
Stefano Zanotti ◽  
Lauren Schilling ◽  
Ernesto Canalis
Keyword(s):  
T Cells ◽  
Osteoclast Differentiation ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
And Function

scholarly journals Compromised Function of Regulatory T Cells in Rheumatoid Arthritis and Reversal by Anti-TNFα Therapy

2004 ◽  
Vol 200 (3) ◽  
pp. 277-285 ◽  
Author(s):  
Michael R. Ehrenstein ◽  
Jamie G. Evans ◽  
Animesh Singh ◽  
Samantha Moore ◽  
Gary Warnes ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Regulatory T Cells ◽  
Significant Rise ◽  
Activated T Cells ◽  
Reactive Protein ◽  
Suppressive Phenotype ◽  
Factor Α

Regulatory T cells have been clearly implicated in the control of disease in murine models of autoimmunity. The paucity of data regarding the role of these lymphocytes in human autoimmune disease has prompted us to examine their function in patients with rheumatoid arthritis (RA). Regulatory (CD4+CD25+) T cells isolated from patients with active RA displayed an anergic phenotype upon stimulation with anti-CD3 and anti-CD28 antibodies, and suppressed the proliferation of effector T cells in vitro. However, they were unable to suppress proinflammatory cytokine secretion from activated T cells and monocytes, or to convey a suppressive phenotype to effector CD4+CD25− T cells. Treatment with antitumor necrosis factor α (TNFα; Infliximab) restored the capacity of regulatory T cells to inhibit cytokine production and to convey a suppressive phenotype to “conventional” T cells. Furthermore, anti-TNFα treatment led to a significant rise in the number of peripheral blood regulatory T cells in RA patients responding to this treatment, which correlated with a reduction in C reactive protein. These data are the first to demonstrate that regulatory T cells are functionally compromised in RA, and indicate that modulation of regulatory T cells by anti-TNFα therapy may be a further mechanism by which this disease is ameliorated.

IL15 Enhances Proliferation and Effector Function of Antigen-Specific Cytotoxic T Lymphocytes (CTLs) and Mitigates the Suppressive Action of Regulatory T Cells (Tregs).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4088-4088
Author(s):  
Serena Kimi Perna ◽  
Biagio De Angelis ◽  
Daria Pagliara ◽  
Lan Zhan ◽  
Cliona M Rooney ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Tumor Cells ◽  
Residual Tumor ◽  
Facs Analysis ◽  
Activated T Cells ◽  
Specific Ctls ◽  
Infected Cells ◽  
And Function

Abstract Abstract 4088 Poster Board III-1023 Although adoptive transfer of antigen-specific CTLs is generally safe and can be clinically effective for the treatment of several malignancies, the administration of stimulatory cytokines may be required to sustain their long-term growth and persistence in vivo. IL2, a γ-chain T-cell growth cytokine, has been used clinically, but is associated with significant toxicities. In addition, IL2 supports the expansion and function of Tregs, counterbalancing its stimulatory effects on CTLs and favoring the establishment of an immune-protected microenvironment for cancer. IL15, like IL2, is a γ-chain cytokine capable of sustaining the expansion and function of effector T cells. We have explored whether this cytokine also shares with IL2 an unwanted stimulatory effect on Tregs. Naturally occurring Tregs (CD4+CD25bright) were isolated from buffy coat preparations from healthy volunteers (mean of Treg recovery: 0.7% ± 0.05% of the starting population of mononuclear cells). The suppressive function of isolated Tregs was confirmed by their ability to inhibit the proliferation of activated T lymphocytes labeled with carboxyfluorescin diacetate succinimidyl ester (CFSE) using FACS analysis to measure CFSE dilution after 5-6 days of culture (activated T cell:Treg ratio 1:1). The proliferation of activated T cells in the presence of Tregs was significantly reduced (28%±5%) as compared to activated T cells cultured in the presence of control CD4+CD25– T cells (59%±5%) (p<0.05). Following addition of IL15 (2.5 ng/mL), however, proliferation of activated T cells continued even in the presence of Tregs (83%±5% plus IL15 without Tregs vs. 80%±5% plus IL15 and Tregs) (p=0.9), suggesting that this cytokine mitigates the immunosuppressive effects of Tregs. We then analyzed whether Tregs affected the anti-tumor activity of antigen-specific CTLs. We used our Epstein-Barr-Virus-(EBV)-specific CTLs as tumor model. EBV-CTLs were co-cultured with EBV-infected cells (LCLs) (CTL:LCL ratio 1:2). Residual tumor cells were enumerated by FACS analysis after 5-7 days of culture. In the absence of exogenous IL-15, EBV-CTLs failed to eliminate EBV-infected cells (residual LCLs: 37%±8%), while the addition of IL15 (2.5 ng/mL) increased the anti-tumor effect of CTLs, so that only 4%±1% tumor cells were detectable at the end of the culture. We then explored the effects of adding Treg to the cultures (Treg:CTL ratio 1:1). The percentage of tumor cells increased rather than decreased by day 5-7 when CTLs were cultured with Tregs in the absence of IL15 (residual tumor cells from 37%±8% in the absence of Tregs to 53%±9% in the presence of Tregs) (p<0.05). When IL15 was added, Treg were more limited in their ability to inhibit T effector cells, so that residual tumor cells were 4%±1% and 11%±3% % in the absence or in the presence of Tregs, respectively. To discover if IL15 has a direct effect on Tregs, we analyzed STAT5 phosphorylation after exposing Tregs to the cytokine. We found that this molecule was phosphorylated in 47%±18% of Tregs 15 minutes after exposure to IL15 (2.5 ng/mL). This effect was mediated by the specific interaction of the cytokine with its own receptor, as no phosphorylation occurred when Treg cells were pre-incubated with an IL-15Rα blocking antibody. This action on Tregs notwithstanding, IL15 stimulation did not modulate Treg inhibitory function, since these cells, even after exposure to IL15 (2.5 ng/mL) for 3-5 days, continued to significantly inhibit the proliferation of T lymphocytes activated in the absence of IL-15 (74%±17% inhibition). Hence, IL15 enhance the proliferative and anti-tumor effects of antigen-specific CTLs, and these effects are not impaired by the presence of Tregs. Administration of IL15 may therefore benefit patients receiving adoptive T cell therapies. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document