The antimalarial action of FK506 and rapamycin: evidence for a direct effect on FK506-binding protein PfFKBP35

Parasitology ◽  
2017 ◽  
Vol 144 (7) ◽  
pp. 869-876 ◽  
Author(s):  
PAUL MONAGHAN ◽  
DARREN B. LENEGHAN ◽  
WESLEY SHAW ◽  
ANGUS BELL
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Antimalarial Activity ◽  
Indirect Evidence ◽  
Inhibitory Effect ◽  
Immunosuppressive Drugs ◽  
Fk506 Binding Protein ◽  
Fk506 Binding Proteins ◽  
Antimalarial Action

SUMMARYFK506 and rapamycin (Rap) are immunosuppressive drugs that act principally on T-lymphocytes. The receptors for both drugs are FK506-binding proteins (FKBPs), but the molecular mechanisms of immunosuppression differ. An FK506–FKBP complex inhibits the protein phosphatase calcineurin, blocking a key step in T-cell activation, while the Rap –FKBP complex binds to the protein kinase target of rapamycin (TOR), which is involved in a subsequent signalling pathway. Both drugs, and certain non-immunosuppressive compounds related to FK506, have potent antimalarial activity. There is however conflicting evidence on the involvement of Plasmodium calcineurin in the action of FK506, and the parasite lacks an apparent TOR homologue. We therefore set out to establish whether inhibition of the Plasmodium falciparum FKBP PfFKBP35 itself might be responsible for the antimalarial effects of FK506 and Rap. Similarities in the antiparasitic actions of FK506 and Rap would constitute indirect evidence for this hypothesis. FK506 and Rap acted indistinguishably on: (i) specificity for different intra-erythrocytic stages in culture, (ii) kinetics of killing or irreversible growth arrest of parasites and (iii) interactions with other antimalarial agents. Furthermore, PfFKBP35's inhibitory effect on calcineurin was independent of FK506 under a range of conditions, suggesting that calcineurin is unlikely to be involved in the antimalarial action of FK506.

MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2

Blood ◽  
2009 ◽  
Vol 113 (26) ◽  
pp. 6576-6583 ◽  
Author(s):  
Grazia Maria Spaggiari ◽  
Heba Abdelrazik ◽  
Flavio Becchetti ◽  
Lorenzo Moretta
Keyword(s):  
Prostaglandin E2 ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Inhibitory Effect ◽  
Interleukin 4 ◽  
Myeloid Dendritic Cells ◽  
And Function ◽  
Dc Maturation

Abstract Various studies analyzed the inhibitory effect exerted by mesenchymal stem cells (MSCs) on cells of the innate or acquired immunity. Myeloid dendritic cells (DCs) are also susceptible to such inhibition. In this study, we show that MSCs strongly inhibit DC generation from peripheral blood monocytes. In the presence of MSCs, monocytes supplemented with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) did not acquire the surface phenotype typical of immature (CD14−, CD1a+) or mature (CD80+, CD86+, CD83+) DCs, failed to produce IL-12, and did not induce T-cell activation or proliferation. Analysis of the molecular mechanism(s) responsible for the inhibitory effect revealed a major role of prostaglandin E2 (PGE2). Thus, addition of the PGE2 inhibitor NS-398 restored DC differentiation and function. Moreover, PGE2 directly added to cultures of monocytes blocked their differentiation toward DCs in a manner similar to MSCs. Although IL-6 has been proposed to play a role in MSC-mediated inhibition of DC differentiation, our data indicate that PGE2 and not IL-6 represents the key inhibitory mediator. Indeed, NS-398 inhibited PGE2 production and restored DC differentiation with no effect on IL-6 production. These data emphasize the role of MSCs in inhibiting early DC maturation and identifying the molecular mechanisms responsible for the inhibitory effect.

scholarly journals Immunomodulatory Effects of Polysaccharide from Marine FungusPhoma herbarumYS4108 on T Cells and Dendritic Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Song Chen ◽  
Ran Ding ◽  
Yan Zhou ◽  
Xian Zhang ◽  
Rui Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Interleukin 12 ◽  
Related Factors ◽  
Knock Out ◽  
Specific Immunity

YCP, as a kind of natural polysaccharides from the mycelium of marine filamentous fungusPhoma herbarumYS4108, has great antitumor potentialviaenhancement of host immune response, but little is known about the molecular mechanisms. In the present study, we mainly focused on the effects and mechanisms of YCP on the specific immunity mediated by dendritic cells (DCs) and T cells. T cell /DC activation-related factors including interferon- (IFN-)γ, interleukin-12 (IL-12), and IL-4 were examined with ELISA. Receptor knock-out mice and fluorescence-activated cell sorting are used to analyze the YCP-binding receptor of T cells and DCs. RT-PCR is utilized to measure MAGE-A3 for analyzing the tumor-specific killing effect. In our study, we demonstrated YCP can provide the second signal for T cell activation, proliferation, and IFN-γproduction through binding to toll-like receptor- (TLR-) 2 and TLR-4. YCP could effectively promote IL-12 secretion and expression of markers (CD80, CD86, and MHC II)viaTLR-4 on DCs. Antigen-specific immunity against mouse melanoma cells was strengthened through the activation of T cells and the enhancement of capacity of DCs by YCP. The data supported that YCP can exhibit specific immunomodulatory capacity mediated by T cells and DCs.

scholarly journals Ubiquitination in T-Cell Activation and Checkpoint Inhibition: New Avenues for Targeted Cancer Immunotherapy

2021 ◽  
Vol 22 (19) ◽  
pp. 10800
Author(s):  
Shubhangi Gavali ◽  
Jianing Liu ◽  
Xinyi Li ◽  
Magdalena Paolino
Keyword(s):  
T Cell ◽  
Patient Outcomes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Cancer Therapeutics ◽  
Patient Treatment ◽  
Functional Roles ◽  
Protein Ubiquitination ◽  
Fine Tune

The advent of T-cell-based immunotherapy has remarkably transformed cancer patient treatment. Despite their success, the currently approved immunotherapeutic protocols still encounter limitations, cause toxicity, and give disparate patient outcomes. Thus, a deeper understanding of the molecular mechanisms of T-cell activation and inhibition is much needed to rationally expand targets and possibilities to improve immunotherapies. Protein ubiquitination downstream of immune signaling pathways is essential to fine-tune virtually all immune responses, in particular, the positive and negative regulation of T-cell activation. Numerous studies have demonstrated that deregulation of ubiquitin-dependent pathways can significantly alter T-cell activation and enhance antitumor responses. Consequently, researchers in academia and industry are actively developing technologies to selectively exploit ubiquitin-related enzymes for cancer therapeutics. In this review, we discuss the molecular and functional roles of ubiquitination in key T-cell activation and checkpoint inhibitory pathways to highlight the vast possibilities that targeting ubiquitination offers for advancing T-cell-based immunotherapies.

scholarly journals Early Pro-Inflammatory Signal and T-Cell Activation Associate With Vaccine-Induced Anti-Vaccinia Protective Neutralizing Antibodies

2021 ◽  
Vol 12 ◽  
Author(s):  
Jue Hou ◽  
Shuhui Wang ◽  
Dan Li ◽  
Lindsay N. Carpp ◽  
Tong Zhang ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Neutralizing Antibodies ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Neutralizing Antibody ◽  
Activator Protein 1 ◽  
Successful Vaccine ◽  
Hiv 1 ◽  
Core Genes

Both vaccine “take” and neutralizing antibody (nAb) titer are historical correlates for vaccine-induced protection from smallpox. We analyzed a subset of samples from a phase 2a trial of three DNA/HIV-1 primes and a recombinant Tiantan vaccinia virus-vectored (rTV)/HIV-1 booster and found that a proportion of participants showed no anti-vaccinia nAb response to the rTV/HIV-1 booster, despite successful vaccine “take.” Using a rich transcriptomic and vaccinia-specific immunological dataset with fine kinetic sampling, we investigated the molecular mechanisms underlying nAb response. Blood transcription module analysis revealed the downregulation of the activator protein 1 (AP-1) pathway in responders, but not in non-responders, and the upregulation of T-cell activation in responders. Furthermore, transcriptional factor network reconstruction revealed the upregulation of AP-1 core genes at hour 4 and day 1 post-rTV/HIV-1 vaccination, followed by a downregulation from day 3 until day 28 in responders. In contrast, AP-1 core and pro-inflammatory genes were upregulated on day 7 in non-responders. We speculate that persistent pro-inflammatory signaling early post-rTV/HIV-1 vaccination inhibits the nAb response.

scholarly journals COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression

2020 ◽  
Vol 75 (7) ◽  
pp. 1667-1670 ◽  
Author(s):  
Dan Zhou ◽  
Sheng-Ming Dai ◽  
Qiang Tong
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Distress Syndrome ◽  
Antiviral Effect ◽  
Inhibitory Effect ◽  
Clinical Use ◽  
Cytokine Release ◽  
Novel Coronavirus ◽  
Effective Drugs ◽  
Preventive Effects

Abstract A novel coronavirus disease (COVID-19), caused by infection with SARS-CoV-2, has swept across 31 provinces in China and over 40 countries worldwide. The transition from first symptoms to acute respiratory distress syndrome (ARDS) is highly likely to be due to uncontrolled cytokine release. There is an urgent need to identify safe and effective drugs for treatment. Chloroquine (CQ) exhibits a promising inhibitory effect. However, the clinical use of CQ can cause severe side effects. We propose that hydroxychloroquine (HCQ), which exhibits an antiviral effect highly similar to that of CQ, could serve as a better therapeutic approach. HCQ is likely to attenuate the severe progression of COVID-19, inhibiting the cytokine storm by suppressing T cell activation. It has a safer clinical profile and is suitable for those who are pregnant. It is cheaper and more readily available in China. We herein strongly urge that clinical trials are performed to assess the preventive effects of HCQ in both disease infection and progression.

scholarly journals Jaw Periosteal Cells Seeded in Beta-Tricalcium Phosphate Inhibit Dendritic Cell Maturation

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 887
Author(s):  
Jingtao Dai ◽  
Felix Umrath ◽  
Siegmar Reinert ◽  
Dorothea Alexander
Keyword(s):  
Gene Expression ◽  
T Cell Activation ◽  
Tricalcium Phosphate ◽  
Cell Activation ◽  
Interleukin 10 ◽  
Inhibitory Effect ◽  
Dendritic Cell Maturation ◽  
Interleukin 12 ◽  
Protein Levels ◽  
Beta Tricalcium Phosphate

Mesenchymal stem cells (MSCs) have gained attraction not only in the field of regenerative medicine but also in the field of autoimmune disease therapies or organ transplantation due to their immunoregulatory and/or immunosuppressive features. Dendritic cells (DCs) play a crucial role in initiating and regulating immune reactions by promoting antigen-specific T cell activation. In this study, we investigated the effect of human jaw periosteal progenitor cells (JPCs) seeded in beta-tricalcium phosphate (β-TCP) scaffolds on monocyte-derived DC differentiation. Significantly lower numbers of differentiated DCs were observed in the presence of normal (Co) and osteogenically induced (Ob) JPCs-seeded β-TCP constructs. Gene expression analysis revealed significantly lower interleukin-12 subunit p35 (IL-12p35) and interleukin-12 receptor beta 2 (IL-12Rβ2) and pro-inflammatory cytokine interferon-gamma (IFN-γ) levels in DCs under Ob conditions, while interleukin-8 (IL-8) gene levels were significantly increased. Furthermore, in the presence of JPCs-seeded β-TCP constructs, interleukin-10 (IL-10) gene expression was significantly induced in DCs, particularly under Ob conditions. Analysis of DC protein levels shows that granulocyte-colony stimulating factor (G-CSF) was significantly upregulated in coculture groups. Our results indicate that undifferentiated and osteogenically induced JPCs-seeded β-TCP constructs have an overall inhibitory effect on monocyte-derived DC maturation.

scholarly journals Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance

2014 ◽  
Vol 112 (2) ◽  
pp. E156-E165 ◽  
Author(s):  
Roberto A. Maldonado ◽  
Robert A. LaMothe ◽  
Joseph D. Ferrari ◽  
Ai-Hong Zhang ◽  
Robert J. Rossi ◽  
...  
Keyword(s):  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Coagulation Factor ◽  
Immunological Tolerance ◽  
Immunosuppressive Drugs ◽  
Free Form ◽  
Peptide Antigens ◽  
Humoral Immune ◽  
Novel Approach

Current treatments to control pathological or unwanted immune responses often use broadly immunosuppressive drugs. New approaches to induce antigen-specific immunological tolerance that control both cellular and humoral immune responses are desirable. Here we describe the use of synthetic, biodegradable nanoparticles carrying either protein or peptide antigens and a tolerogenic immunomodulator, rapamycin, to induce durable and antigen-specific immune tolerance, even in the presence of potent Toll-like receptor agonists. Treatment with tolerogenic nanoparticles results in the inhibition of CD4+ and CD8+ T-cell activation, an increase in regulatory cells, durable B-cell tolerance resistant to multiple immunogenic challenges, and the inhibition of antigen-specific hypersensitivity reactions, relapsing experimental autoimmune encephalomyelitis, and antibody responses against coagulation factor VIII in hemophilia A mice, even in animals previously sensitized to antigen. Only encapsulated rapamycin, not the free form, could induce immunological tolerance. Tolerogenic nanoparticle therapy represents a potential novel approach for the treatment of allergies, autoimmune diseases, and prevention of antidrug antibodies against biologic therapies.

Enhanced B7-2 Gene Expression by Interferon-γ in Human Monocytic Cells Is Controlled Through Transcriptional and Posttranscriptional Mechanisms

Blood ◽  
1999 ◽  
Vol 94 (5) ◽  
pp. 1782-1789 ◽  
Author(s):  
R.E. Curiel ◽  
C.S. Garcia ◽  
S. Rottschafer ◽  
M.C. Bosco ◽  
I. Espinoza-Delgado
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Costimulatory Molecule ◽  
Interferon Γ ◽  
Monocytic Cell ◽  
Monocytic Cells ◽  
Enhanced Expression ◽  
Ifn Γ

B7-2 is a costimulatory molecule expressed on professional antigen-presenting cells that provides T cells with a critical signal resulting in T-cell activation. Interferon-γ (IFN-γ) enhances B7-2 protein expression in monocytic cells. However, the molecular mechanisms controlling the enhanced expression of B7-2 are poorly understood. Northern blot and flow cytometry analysis revealed that human monocytes and the human monocytic cell line MonoMac6 (MM6) constitutively expressed B7-2 mRNA and protein and IFN-γ treatment further enhanced the expression of both molecules. The ability of IFN-γ to enhance B7-2 mRNA was evident at the dose of 31 U/mL and reached plateau levels at 500 U/mL. The effects of IFN-γ on B7-2 mRNA expression were time dependent and occurred within 3 hours of treatment and increased through 24 hours. In vitro transcription assays and mRNA stability experiments showed that IFN-γ increases both transcriptional activity and the stability of B7-2 mRNA. Treatment of MM6 cells with cycloheximide showed that de novo protein synthesis was not required for the IFN-γ–enhanced expression of B7-2 mRNA. Overall, these studies show for the first time that IFN-γ–enhanced expression of B7-2 protein in human monocytic cells is controlled at the gene level through a dual mechanism involving transcriptional and posttranscriptional mechanisms.

The Impact of Immunosuppressive Drugs on the Analysis of T-Cell Activation

2000 ◽  
Vol 7 (7) ◽  
pp. 673-692 ◽  
Author(s):  
Paula Rovira ◽  
Laurent Mascarell ◽  
Paolo Bachi
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunosuppressive Drugs ◽  
The Impact

scholarly journals Twisted gastrulation (Tsg) is regulated by Tob and enhances TGF-β signaling in activated T lymphocytes

Blood ◽  
2006 ◽  
Vol 109 (7) ◽  
pp. 2944-2952 ◽  
Author(s):  
Dimitrios Tzachanis ◽  
Lequn Li ◽  
Esther M. Lafuente ◽  
Alla Berezovskaya ◽  
Gordon J. Freeman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Direct Interaction ◽  
Subtractive Hybridization ◽  
Inhibitory Effect ◽  
Twisted Gastrulation ◽  
Quiescent T Cells

Abstract Quiescent T cells express Tob, an APRO gene family member, which functions as a transcriptional regulator. Subtractive hybridization identified Twisted gastrulation (Tsg) as one of the genes suppressed by Tob. Tsg is a secreted protein that interacts with Drosophila decapentaplegic (Dpp) and its vertebrate orthologs BMP2/4 and regulates morphogenetic effects in embryos. Here, we report the expression and function of Tsg in human T cells. Tsg mRNA was almost undetectable in unstimulated T cells and was up-regulated after activation by TCR/CD3 and either CD28, IL-2, or PMA. Tsg protein had no effect on responses of primary T cells to TCR/CD3 stimulation but had a potent inhibitory effect on proliferation and cytokine production of primed alloreactive CD4+ cells. Surprisingly, Tsg did not affect phosphorylation of the BMP-specific Smad1 but induced phosphorylation of the TGF-β–specific Smad2 and mediated DNA binding on Smad3/4 consensus-binding sites, suggesting that it acted downstream of TGF-β. In vitro association assays revealed a direct interaction of Tsg and TGF-β proteins. Thus, Tsg functions as an agonist synergizing with TGF-β to inhibit T-cell activation. Modulation of Tsg signaling may represent a novel target for molecular intervention toward control of aberrant T-cell responses during ongoing graft-versus-host disease (GVHD) and autoimmune diseases.

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