Plasmacytoid Dendritic Cells and the Control of Herpesvirus Infections

Type-I interferons (IFN-I) are cytokines essential for vertebrate antiviral defense, including against herpesviruses. IFN-I have potent direct antiviral activities and also mediate a multiplicity of immunoregulatory functions, which can either promote or dampen antiviral adaptive immune responses. Plasmacytoid dendritic cells (pDCs) are the professional producers of IFN-I in response to many viruses, including all of the herpesviruses tested. There is strong evidence that pDCs could play a major role in the initial orchestration of both innate and adaptive antiviral immune responses. Depending on their activation pattern, pDC responses may be either protective or detrimental to the host. Here, we summarize and discuss current knowledge regarding pDC implication in the physiopathology of mouse and human herpesvirus infections, and we discuss how pDC functions could be manipulated in immunotherapeutic settings to promote health over disease

Natural Killer Cells Promote Early CD8 T Cell Responses against Cytomegalovirus

Understanding the mechanisms that help promote protective immune responses to pathogens is a major challenge in biomedical research and an important goal for the design of innovative therapeutic or vaccination strategies. While natural killer (NK) cells can directly contribute to the control of viral replication, whether, and how, they may help orchestrate global antiviral defense is largely unknown. To address this question, we took advantage of the well-defined molecular interactions involved in the recognition of mouse cytomegalovirus (MCMV) by NK cells. By using congenic or mutant mice and wild-type versus genetically engineered viruses, we examined the consequences on antiviral CD8 T cell responses of specific defects in the ability of the NK cells to control MCMV. This system allowed us to demonstrate, to our knowledge for the first time, that NK cells accelerate CD8 T cell responses against a viral infection in vivo. Moreover, we identify the underlying mechanism as the ability of NK cells to limit IFN-α/β production to levels not immunosuppressive to the host. This is achieved through the early control of cytomegalovirus, which dramatically reduces the activation of plasmacytoid dendritic cells (pDCs) for cytokine production, preserves the conventional dendritic cell (cDC) compartment, and accelerates antiviral CD8 T cell responses. Conversely, exogenous IFN-α administration in resistant animals ablates cDCs and delays CD8 T cell activation in the face of NK cell control of viral replication. Collectively, our data demonstrate that the ability of NK cells to respond very early to cytomegalovirus infection critically contributes to balance the intensity of other innate immune responses, which dampens early immunopathology and promotes optimal initiation of antiviral CD8 T cell responses. Thus, the extent to which NK cell responses benefit the host goes beyond their direct antiviral effects and extends to the prevention of innate cytokine shock and to the promotion of adaptive immunity

A minimal BV action for Vasiliev's four-dimensional higher spin gravity

The action principle for Vasiliev's four-dimensional higher-spin gravity proposed recently by two of the authors, is converted into a minimal BV master action using the AKSZ procedure, which amounts to replacing the classical differential forms by vectorial superfields of fixed total degree given by the sum of form degree and ghost number. The nilpotency of the BRST operator is achieved by imposing boundary conditions and choosing appropriate gauge transitions between charts leading to a globally-defined formulation based on a principal bundle.Comment: 39 pages, 1 figure. Additional comments in the conclusion

Etude in vivo des cellules dendritiques plasmacytoïdes murines à l'infection par le cytomégalovirus murin

Les cellules dendritiques plasmacytoïdes (pDC) sont caractérisés par leur habilité à produire rapidement de forts taux d'interféron de type I (IFN-I) en réponse à de nombreux virus, notamment lors de l'infection in vivo par le cytomégalovirus murin (MCMV). Les pDC contribuent aussi à la production d'autres cytokines. Cependant, leur relative contribution pour ces fonctions comparées à d'autres celliles n'est pas clairement établie. en outre, le rôle global des pDC dnas la réistance de l'hôte à l'infection virale est difficile à étudier avec rigueur, en partie en raison de l'absence d'une méthode permettant la déplétion efficace et spécifique de ces cellules in vivo. Les expressions de l'IFN-I, de l'IL-2 et du TNF-a ont été examinées par cytométrie en flux multiparamétrique permettant d'identifier les sources cellulaires et les mécanismes molléculaires impliqués pour la production de ce cytokines innées dans divers tissus précocement après l'infection par le MCMV. Les pDC spléniques sont la principale source de cytokines innées précocement après l'infection par le MCMV, avec production simultanée de trois cytokines dans des cellules individuelles. De plus, un rôle redondant de TLR-7 et -9 a été identifié pour la régulation de ces fonctions. Dans le but d'obtenir différents modèles murins conçus pour permettre l'étude rigoureuse des fonctions des pDC, nous sommes sur le point de générer des souris qui exprimeront spécifiquement la recombinase CRE dans les pDC.Plasmacytoid dentritic cells (pDC) are characterized by their ability to rapidly produce high levels of type I interferon (IFN-I) in response to many viruses, especially during in vivo infection by murine cytomegalovirus (MCMV). pDC also contribute to the production of other cytokines. However, their relativecontribution to these functions compared to other cells in unclear. In addtition, the overall role of pDC in the host resistance to viral infection is difficult to study rigorously, partly beacause of the lack beacause of a method for the effective and specific depletion of these cells in vivo. The expressions of IFN-I, IL-2 and TNF-a were examined by multiparameter flow cytometry identify the cellular souces and molecular mechanisms involved in the production if innate cytokines in various tissues early after infection by MCMV. Splenic pDC are the main source of innate cytokines early after infection been identified to regulate these functions. In order to obtain different mouse models designed for the rigorous study of pDC functions, we are about to generate mice that express CRE recombinase specifically in pDC.AIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF

Cutting edge: Overlapping functions of TLR7 and TLR9 for innate defense against a herpesvirus infection.

International audienceAs initially demonstrated with murine cytomegalovirus (MCMV), plasmacytoid dendritic cells (pDCs) are the major source of IFN-alpha/beta in response to a variety of viruses in vivo. However, contradictory results have been obtained pertaining to the mechanisms promoting IFN-alpha/beta production by pDCs in response to MCMV. In this study we show that TLR7 and TLR9 exert redundant functions for IFN-alpha/beta, IL-12p40, and TNF-alpha production by pDCs in vivo during MCMV infection. In contrast, we confirm that systemic production of IL-12p70 strictly depends on TLR9. The combined loss of TLR7 and TLR9 recapitulates critical features of the phenotype of MyD88-deficient mice, including a dramatic decrease in systemic IFN-alpha/beta levels, an increase in viral load, and increased susceptibility to MCMV-induced mortality. This is the first demonstration of the implication of TLR7 in the recognition of a DNA virus

Differential responses of immune cells to type I interferon contribute to host resistance to viral infection.

Type I interferons (IFNs) are central to antiviral defense, but how they orchestrate immune cell function is incompletely understood. We determined that IFNs produced during murine cytomegalovirus (MCMV) infection differentially affect dendritic cells (DCs) and natural killer (NK) cells. IFNs induce cell-intrinsic responses in DCs, activating antiproliferative, antiviral, and lymphocyte-activating gene networks, consistent with high activity of the transcription factor STAT1 in these cells. By comparison, NK cells exhibit lower STAT1 expression and reduced IFN responsiveness. Rather, IFNs indirectly affect NK cells by inducing IL-15, which activates the transcription factor E2F and stimulates genes promoting cell expansion. IFN cell-intrinsic responses are necessary in DCs, but not NK cells, for MCMV resistance. Thus, sensitivity to IFN-induced cytokines and differences in IFN receptor signaling program immune cells to mount distinct responses that promote viral control