LIGHTing up dendritic cell activation: Immune regulation and viral exploitation

Pollara, Gabriele; Katz, David R.; Chain, Benjamin M.

doi:10.1002/jcp.20473

Cited by 16 publications

(15 citation statements)

References 16 publications

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“…One of the known receptors for gD is HVEM (54, 55), a TNF receptor family member that is known to signal via NF-B in response to its natural ligand LIGHT (32)(33)(34)56). Signaling via this receptor might therefore be an essential, although clearly not a sufficient event for DC maturation in our model.…”

Section: Discussionmentioning

confidence: 98%

“…The gD receptor HVEM is a member of the TNF receptor family and is known to transduce activation signals in response to its ligand LIGHT (32)(33)(34). Although gD alone failed to induce DC maturation, it remained possible that gD/HVEM interaction was one essential component in the overall activation process.…”

Section: The DC Response To Hsv-1 Glycoproteins Does Not Require Herpmentioning

confidence: 99%

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Glycoprotein-Dependent and TLR2-Independent Innate Immune Recognition of Herpes Simplex Virus-1 by Dendritic Cells

Reske

Pollara

Krummenacher

et al. 2008

The Journal of Immunology

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Innate immune recognition is an important early event in the host response to herpes simplex virus-1 (HSV-1) infection. Dendritic cells (DC) play an important sentinel role in this recognition. Previous studies have shown that monocyte-derived DC (MDDC) respond to HSV-1 by up-regulation of costimulatory molecules and type I IFN release, but the molecular targets on the virus recognized by the DC have not been defined. In this study we show that MDDC recognize and respond to the four essential viral glycoproteins, gB, gD, and gHgL, independent of other viral proteins or nucleic acids. DC recognition of these four glycoproteins leads to the up-regulation of CD40, CD83, CD86, and HLA-DR and to the production of IFN-α and IL-10, but not IL-12p70. Glutaraldehyde-fixation and nonfunctional gH mutants were used to show that recognition of glycoproteins does not require membrane fusion. The nature of the recognition event was probed further by transfecting glycoproteins individually or in combination, by blocking individual proteins with Abs, or by using mutant gD constructs unable to bind to their known cognate receptors. Unexpectedly, MDDC responses were found to require expression of all four glycoproteins. Furthermore, gD mutants that cannot bind nectin-1 and/or herpesvirus entry mediator can still induce DC maturation. Finally, although HSV-1 can signal via the TLR2 receptor, this receptor does not mediate recognition of glycoproteins. Thus, the complex of the four essential HSV-1 entry glycoproteins on the cell surface can provide a target for innate immune recognition of this virus.

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Section: Discussionmentioning

confidence: 98%

Section: The DC Response To Hsv-1 Glycoproteins Does Not Require Herpmentioning

confidence: 99%

Glycoprotein-Dependent and TLR2-Independent Innate Immune Recognition of Herpes Simplex Virus-1 by Dendritic Cells

Reske

Pollara

Krummenacher

et al. 2008

The Journal of Immunology

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“…No anti-host CTL activity was generated in the mice injected with HVEM-KO cells, in striking contrast to the ample CTL activity induced by a transfer of control lymphocytes ( Figure 4A). Considering the expression and function of HVEM on broad immune populations, including DC, T, and B cells, 32,33 we further dissected the functional role of HVEM on donor T and non-T cells using experiments similar to those described in Figure 1B. Anti-host CTL activity was completely abrogated when HVEM-KO T cells were transferred as donor cells, irrespective of the genotypes of cotransferred non-T cells, whereas a lack of HVEM on non-T cells did not hamper CTL generation when cotransferred with WT T cells ( Figure 4B).…”

Section: Essential Role Of Hvem On Donor T Cells In Their Survivalmentioning

confidence: 99%

Selective targeting of the LIGHT-HVEM costimulatory system for the treatment of graft-versus-host disease

Flies

et al. 2006

Blood

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Decoy lymphotoxin ␤ receptor (LT␤R) has potent immune inhibitory activities and thus represents a promising biologic for the treatment of inflammation, autoimmune diseases, and graft-versus-host disease (GVHD). As this reagent interrupts multiple molecular interactions, including LT␤-LT␤R and LIGHT-HVEM/LT␤R, underlying molecular mechanisms have yet to be fully understood. In this study, we demonstrate that blockade of the LIGHT-HVEM pathway is sufficient to induce amelioration of GVHD in mouse models. Anti-host cytotoxic T lymphocyte (CTL)activity IntroductionThe functional network of tumor necrosis factor (TNF) and TNF receptor superfamily members is composed of complex cross-talk between multiple ligands and multiple receptors, which regulate pleiotropic functions in the immune system. 1 LIGHT, standing for homologous to lymphotoxins, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes, is a type II transmembrane glycoprotein belonging to the TNF ligand superfamily. 2 LIGHT is expressed on immature dendritic cells (DCs) and activated T cells 2,3 and interacts with 2 functional receptors, lymphotoxin-␤ receptor (LT␤R) and HVEM. 2 LIGHT interaction with LT␤R triggers the production of proinflammatory mediators, 4,5 up-regulates adhesion molecule expression, 6 and induces apoptotic cell death in certain tumors. 7 On the other hand, by signaling through HVEM, LIGHT costimulates T-cell activation. 8 In vivo experiments demonstrated that transgenic expression of LIGHT leads to spontaneous progression of inflammatory autoimmunity such as Crohn disease, 9-11 while genetic disruption of LIGHT results in impaired T-cell activation, particularly in CD8 ϩ T cells, [12][13][14][15] and renders mice less vulnerable to pathogenic inflammation, as shown in acute hepatitis models. 16 Thus, LIGHT regulates multiple immune functions of innate and adaptive immunity through interactions with LT␤R and HVEM.There are numerous reports demonstrating therapeutic effects of decoy protein of LT␤R in various immunologic diseases, including autoimmunity, inflammation, and transplantation, 17,18 indicating that decoy LT␤R could be a potential biologic for clinical immunotherapy, analogous to a decoy form of TNF-receptor. 19 Prolonged administration of decoy LT␤R, however, might become a double-edged sword since it abrogates the maintenance of DC and natural killer/natural killer T (NK/NKT) cells 20,21 and inhibits the microstructure formation of lymphoid organs, 22 thus disrupting immune homeostasis. Therefore, it is of great interest to discover novel approaches that separate the therapeutic effects of decoy LT␤R from the potential adverse effects. While decoy LT␤R interferes with 3 molecular interactions-LT␤-LT␤R, LIGHT-LT␤R, and LIGHT-HVEM-the antihomeostatic effects are largely dependent on LT␤-LT␤R functions since the corresponding phenotypes are observed in LT␤-or LT␤R-KO mice but not in LIGHT-KO mice. [12][13][14][15][23][2...

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“…As DCs play a central role in both the innate and adaptive immune systems, they represent a potential target for different pathogens to evade host immune responses [Jenne et al, 2001;Steinman and Nussenzweig, 2002;Pollara et al, 2005]. Several groups have demonstrated that the functionality of DCs is altered during the course of viral infections.…”

Section: Discussionmentioning

confidence: 99%

Woodchuck dendritic cells generated from peripheral blood mononuclear cells and transduced with recombinant human adenovirus serotype 5 induce antigen‐specific cellular immune responses

Ochoa-Callejero

Berraondo

Crettaz

et al. 2007

Journal of Medical Virology

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Woodchucks infected with the woodchuck hepatitis virus (WHV) is the best available animal model for testing the immunotherapeutic effects of dendritic cells (DCs) in the setting of a chronic infection, as woodchucks develop a persistent infection resembling that seen in humans infected with the hepatitis B virus. In the present study, DCs were generated from woodchuck peripheral blood mononuclear cells (wDCs) in the presence of human granulocyte macrophage colony-stimulating factor (hGM-CSF) and human interleukin 4 (hIL-4). After 7 days of culture, cells with morphology similar to DCs were stained positively with a cross-reactive anti-human CD86 antibody. Functional analysis showed that uptake of FITC-dextran by wDCs was very efficient and was partially inhibited after LPS-induced maturation. Furthermore, wDCs stimulated allogenic lymphocytes and induced proliferation. Moreover, wDCs were transduced efficiently with a human adenovirus serotype 5 for the expression of beta-galactosidase. Following transduction and in vivo administration of such DCs into woodchucks, an antigen-specific cellular immune response was induced. These results demonstrate that wDCs can be generated from the peripheral blood. Following transfection with a recombinant adenovirus wDCs can be used as a feasible and effective tool for eliciting WHV-specific T-cell responses indicating their potential to serve as prophylactic and therapeutic vaccines.

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LIGHTing up dendritic cell activation: Immune regulation and viral exploitation

Cited by 16 publications

References 16 publications

Glycoprotein-Dependent and TLR2-Independent Innate Immune Recognition of Herpes Simplex Virus-1 by Dendritic Cells

Glycoprotein-Dependent and TLR2-Independent Innate Immune Recognition of Herpes Simplex Virus-1 by Dendritic Cells

Selective targeting of the LIGHT-HVEM costimulatory system for the treatment of graft-versus-host disease

Woodchuck dendritic cells generated from peripheral blood mononuclear cells and transduced with recombinant human adenovirus serotype 5 induce antigen‐specific cellular immune responses

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