Identification of crassin acetate as a new immunosuppressant triggering heme oxygenase-1 expression in dendritic cells

Abstract By screening 720 natural compounds in a standard 2-way allogeneic mixed leukocyte reaction assay, we identified a potent immunosuppressive capacity of crassin acetate (CRA), a coral-derived cembrane diterpenoid. CRA efficiently inhibited allogeneic mixed leukocyte reaction as well as antigen-specific activation of CD4 T cells by bone marrow–derived dendritic cells (DCs). With regard to cellular targets, CRA suppressed not only mitogen-triggered T-cell activation, but also lipopolysaccharide-induced DC maturation, indicating dual functionality. Treatment with CRA at nontoxic doses induced heme oxygenase-1 (HO-1) mRNA/protein expression and HO-1 enzymatic activity in DCs, suggesting a unique mechanism of action. In fact, lipopolysaccharide-induced DC maturation was also inhibited by structurally unrelated compounds known to induce HO-1 expression or carbon monoxide (CO) release. Allergic contact hypersensitivity response to oxazolone and oxazolone-induced Langerhans cell migration from epidermis were both prevented almost completely by systemic administration of CRA. Not only do our results support the recent concept that HO-1/CO system negatively regulates immune responses, they also form both conceptual and technical frameworks for a more systematic, large-scale drug discovery effort to identify HO-1/CO-targeted immunosuppressants with dual target specificity.

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Abstract 760: Heme Oxygenase-1 expression in Dendritic Cells determines the Outcome of Transplantation Arteriosclerosis

Circulation ◽

10.1161/circ.116.suppl_16.ii_146 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Annemarie Noordeloos ◽

Elza van Deel ◽

Denise Hermes ◽

Maarten L Simoons ◽

Dirk J Duncker ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Heme Oxygenase ◽

T Cell Activation ◽

Neointimal Hyperplasia ◽

Cd4 T Cell ◽

Cell Infiltration ◽

Heme Oxygenase 1 ◽

T Cell Infiltration ◽

Mhcii Expression

Introduction: Although expression of heme oxygenase-1 (HO1) attenuates transplantation arteriosclerosis, the mechanism by which HO1 exerts its protective effect remains unclear. We studied the effect of HO1-deficient vs. wildtype (WT) dendritic cells (DCs) on the T-cell priming response and outcome in a murine transplant arteriosclerosis model. Methods: At day 0 C57bl6 mice received either WT (n=6) or HO1-knockout DCs (n=6) pre-sensitized with Balb/c splenocytes lysate to accelerate the development of arteriosclerosis. At day 10 an aorta segment from Balb/c mice was transplanted into the carotid artery position of C57Bl6 mice.14 days after transplantation allografts were excised and processed for immunohistochemical analysis. Results: HO1-deficient DCs significantly increased neointimal hyperplasia as compared to WT DCs (116995 vs. 46114μm 2 P<0.05) and incidence of intima formation (83 vs. 50% in WT DC). HO1 deficient DCs also increased medial thickeness (15936 vs.12034 μm 2 P<0.05) and intimal VSMCs content (76 vs. 46% P<0.05) and resulted in more prominent medial cell infiltration (461μm 2 vs. 232μm 2 P<0.05). Although HO1 deficient and WT DCs could be detected in allografts, HO1-nullizygous DCs induced an increase in CD4+ T-cell infiltration (9.5 vs. 0.1% in WT P<0.05) concomitant to a decrease of CD8+ T cell infiltration (8 vs.14%, P<0.05). In line with these observations Affymetrix microarray analysis confirmed that HO1 deletion in DCs was associated with a significant downregulation of MHCII-H2A expression (associated with CD4+T-cell activation) and induction of inhibitors of MHCII expression (including IK protein) whereas MHC I expression remained unchanged. Conclusions: HO1 expression in dendritic cells increases vascular cell infiltration with a higher CD8+/CD4+ T-cell ratio by stabilizing MHCII expression in vascular allografts resulting in inhibition of neointima formation and hence improved allograft survival.

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Involvement of heme oxygenase-1 in suppression of T cell activation by quercetin

Immunopharmacology and Immunotoxicology ◽

10.1080/08923973.2020.1759623 ◽

2020 ◽

Vol 42 (4) ◽

pp. 295-305

Author(s):

Tomoshi Sugiyama ◽

Miyoko Matsushima ◽

Tomoko Ohdachi ◽

Naozumi Hashimoto ◽

Yoshinori Hasegawa ◽

...

Keyword(s):

T Cell ◽

Heme Oxygenase ◽

T Cell Activation ◽

Cell Activation ◽

Heme Oxygenase 1

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Dendritic Cell Responses to Early Murine Cytomegalovirus Infection

Journal of Experimental Medicine ◽

10.1084/jem.20021522 ◽

2003 ◽

Vol 197 (7) ◽

pp. 885-898 ◽

Cited By ~ 272

Author(s):

Marc Dalod ◽

Tanya Hamilton ◽

Rachelle Salomon ◽

Thais P. Salazar-Mather ◽

Stanley C. Henry ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

T Cell Activation ◽

Cell Activation ◽

Lymphocyte Activation ◽

Murine Cytomegalovirus ◽

Cell Responses ◽

Dc Maturation

Differentiation of dendritic cells (DCs) into particular subsets may act to shape innate and adaptive immune responses, but little is known about how this occurs during infections. Plasmacytoid dendritic cells (PDCs) are major producers of interferon (IFN)-α/β in response to many viruses. Here, the functions of these and other splenic DC subsets are further analyzed after in vivo infection with murine cytomegalovirus (MCMV). Viral challenge induced PDC maturation, their production of high levels of innate cytokines, and their ability to activate natural killer (NK) cells. The conditions also licensed PDCs to efficiently activate CD8 T cells in vitro. Non-plasmacytoid DCs induced T lymphocyte activation in vitro. As MCMV preferentially infected CD8α+ DCs, however, restricted access to antigens may limit plasmacytoid and CD11b+ DC contribution to CD8 T cell activation. IFN-α/β regulated multiple DC responses, limiting viral replication in all DC and IL-12 production especially in the CD11b+ subset but promoting PDC accumulation and CD8α+ DC maturation. Thus, during defense against a viral infection, PDCs appear specialized for initiation of innate, and as a result of their production of IFN-α/β, regulate other DCs for induction of adaptive immunity. Therefore, they may orchestrate the DC subsets to shape endogenous immune responses to viruses.

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Effects of Filovirus Interferon Antagonists on Responses of Human Monocyte-Derived Dendritic Cells to RNA Virus Infection

Journal of Virology ◽

10.1128/jvi.00191-16 ◽

2016 ◽

Vol 90 (10) ◽

pp. 5108-5118 ◽

Cited By ~ 18

Author(s):

Benjamin C. Yen ◽

Christopher F. Basler

Keyword(s):

Dendritic Cells ◽

T Cell Activation ◽

Cell Activation ◽

Ebola Virus ◽

Human Monocyte ◽

Marburg Virus ◽

Innate Immune ◽

Dc Maturation

ABSTRACTDendritic cells (DCs) are major targets of filovirus infectionin vivo. Previous studies have shown that the filoviruses Ebola virus (EBOV) and Marburg virus (MARV) suppress DC maturationin vitro. Both viruses also encode innate immune evasion functions. The EBOV VP35 (eVP35) and the MARV VP35 (mVP35) proteins each can block RIG-I-like receptor signaling and alpha/beta interferon (IFN-α/β) production. The EBOV VP24 (eVP24) and MARV VP40 (mVP40) proteins each inhibit the production of IFN-stimulated genes (ISGs) by blocking Jak-STAT signaling; however, this occurs by different mechanisms, with eVP24 blocking nuclear import of tyrosine-phosphorylated STAT1 and mVP40 blocking Jak1 function. MARV VP24 (mVP24) has been demonstrated to modulate host cell antioxidant responses. Previous studies demonstrated that eVP35 is sufficient to strongly impair primary human monocyte-derived DC (MDDC) responses upon stimulation induced through the RIG-I-like receptor pathways. We demonstrate that mVP35, like eVP35, suppresses not only IFN-α/β production but also proinflammatory responses after stimulation of MDDCs with RIG-I activators. In contrast, eVP24 and mVP40, despite suppressing ISG production upon RIG-I activation, failed to block upregulation of maturation markers or T cell activation. mVP24, although able to stimulate expression of antioxidant response genes, had no measurable impact of DC function. These data are consistent with a model where filoviral VP35 proteins are the major suppressors of DC maturation during filovirus infection, whereas the filoviral VP24 proteins and mVP40 are insufficient to prevent DC maturation.IMPORTANCEThe ability to suppress the function of dendritic cells (DCs) likely contributes to the pathogenesis of disease caused by the filoviruses Ebola virus and Marburg virus. To clarify the basis for this DC suppression, we assessed the effect of filovirus proteins known to antagonize innate immune signaling pathways, including Ebola virus VP35 and VP24 and Marburg virus VP35, VP40, and VP24, on DC maturation and function. The data demonstrate that the VP35s from Ebola virus and Marburg virus are the major suppressors of DC maturation and that the effects on DCs of the remaining innate immune inhibitors are minor.

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Single-cell RNA-Seq analysis reveals dual sensing of HIV-1 in blood Axl+ dendritic cells

10.1101/2022.01.03.474732 ◽

2022 ◽

Author(s):

Flavien Brouiller ◽

Francesca Nadalin ◽

Ouardia Aït-Mohamed ◽

Pierre-Emmanuel Bonté ◽

Constance Delaugerre ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell Activation ◽

Cell Activation ◽

Cd4 T Cell ◽

Type I ◽

Rna Seq ◽

Innate Response ◽

Viral Response ◽

Hiv 1 ◽

Dc Maturation

Sensing of incoming viruses represents one of the pivotal tasks of dendritic cells (DC). Human primary blood DC encompass various subsets that are diverse in their susceptibility and response to HIV-1. The recent identification of Axl+DC, a new blood DC subset, endowed with unique capacities to bind, replicate, and transmit HIV-1 prompted us to evaluate its anti-viral response. We show that HIV-1 induced two main broad and intense transcriptional programs in different Axl+DC potentially induced by different sensors; a NF-κB-mediated program that led to DC maturation and efficient antigen-specific CD4+T cell activation, and a program mediated by STAT1/2 that activated type I IFN and an ISG response. These responses were absent from cDC2 exposed to HIV-1 except when viral replication occurred. Finally, Axl+DC actively replicating HIV-1 identified by quantification of viral transcripts exhibited a mixed NF-κB/ISG innate response. Our results suggest that the route of HIV-1 entry may dictate different innate sensing pathway by DC.

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Faculty Opinions recommendation of The brain as an immune privileged site: dendritic cells of the central nervous system inhibit T cell activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1014090.200835 ◽

2003 ◽

Author(s):

Magdalena Plebanski

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Dendritic Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

The Central Nervous System ◽

The Brain ◽

Privileged Site

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Faculty Opinions recommendation of Listeria-infected myeloid dendritic cells produce IFN-beta, priming T cell activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1026752.325366 ◽

2005 ◽

Author(s):

Charles Czuprynski

Keyword(s):

Dendritic Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Myeloid Dendritic Cells

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Faculty Opinions recommendation of Mast cells and dendritic cells form synapses that facilitate antigen transfer for T cell activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725742980.793509477 ◽

2015 ◽

Author(s):

Vivian Tang

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Mast Cells ◽

T Cell Activation ◽

Cell Activation ◽

Antigen Transfer

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CD14 Expressing Precursors Give Rise to Highly Functional Conventional Dendritic Cells for Use as Dendritic Cell Vaccine

Cancers ◽

10.3390/cancers13153818 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3818

Author(s):

Maud Plantinga ◽

Denise A. M. H. van den Beemt ◽

Ester Dünnebach ◽

Stefan Nierkens

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Cord Blood ◽

T Cell Activation ◽

Cell Activation ◽

Ex Vivo ◽

Dendritic Cell Vaccine ◽

Cell Vaccine ◽

Activated T Cells

Induction of long-lasting immunity by dendritic cells (DCs) makes them attractive candidates for anti-tumor vaccination. Although DC vaccinations are generally considered safe, clinical responses remain inconsistent in clinical trials. This initiated studies to identify subsets of DCs with superior capabilities to induce effective and memory anti-tumor responses. The use of primary DCs has been suggested to overcome the functional limitations of ex vivo monocyte-derived DCs (moDC). The ontogeny of primary DCs has recently been revised by the introduction of DC3, which phenotypically resembles conventional (c)DC2 as well as moDC. Previously, we developed a protocol to generate cDC2s from cord blood (CB)-derived stem cells via a CD115-expressing precursor. Here, we performed index sorting and single-cell RNA-sequencing to define the heterogeneity of in vitro developed DC precursors and identified CD14+CD115+ expressing cells that develop into CD1c++DCs and the remainder cells brought about CD123+DCs, as well as assessed their potency. The maturation status and T-cell activation potential were assessed using flow cytometry. CD123+DCs were specifically prone to take up antigens but only modestly activated T-cells. In contrast, CD1c++ are highly mature and specialized in both naïve as well as antigen-experienced T-cell activation. These findings show in vitro functional diversity between cord blood stem cell-derived CD123+DC and CD1c++DCs and may advance the efficiency of DC-based vaccines.

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