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In vivo conversion of BM plasmacytoid DC into CD11b+ conventional DC during virus infection.

ABSTRACT: DC are a highly heterogeneous population that plays a critical role in host defense. We previously demonstrated that virus infection induces BM plasmacytoid DC (pDC) differentiation into CD11b(+) conventional DC (cDC) upon in vitro culture with Fms-like tyrosine kinase 3 ligand (Flt3L). Here we use immunoglobulin D-J rearrangements and pDC adoptive transfer to provide definitive proof supporting BM pDC conversion into CD11b(+) cDC during in vivo viral infection. We show that in vivo BM pDC conversion into CD11b(+) cDC relates to enhanced ability to prime virus-specific T cells. Furthermore, we demonstrate that in vivo pDC conversion does not rely on viral infection of BM pDC, but instead is mediated by type I IFN signaling. Finally, by exploiting recently identified pDC-specific Ab, we provide further characterizations of the BM pDC fraction that exhibits this broader developmental plasticity. Collectively, these data indicate that BM pDC actively contribute to the CD11b(+) cDC pool during in vivo viral infection and delineates molecular, functional, and phenotypic features of this novel developmental pathway.

SUBMITTER: Liou LY

PROVIDER: S-EPMC2897746 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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In vivo conversion of BM plasmacytoid DC into CD11b+ conventional DC during virus infection.

Liou Li-Ying LY Blasius Amanda L AL Welch Megan J MJ Colonna Marco M Oldstone Michael B A MB Zuniga Elina I EI

European journal of immunology 20081201 12

DC are a highly heterogeneous population that plays a critical role in host defense. We previously demonstrated that virus infection induces BM plasmacytoid DC (pDC) differentiation into CD11b(+) conventional DC (cDC) upon in vitro culture with Fms-like tyrosine kinase 3 ligand (Flt3L). Here we use immunoglobulin D-J rearrangements and pDC adoptive transfer to provide definitive proof supporting BM pDC conversion into CD11b(+) cDC during in vivo viral infection. We show that in vivo BM pDC conve ...[more]

PMID: 18979509

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Project description:UnlabelledType I interferons (IFNs) crucially contribute to host survival upon viral infections. Robust expression of type I IFNs (IFN-α/β) and induction of an antiviral state critically depend on amplification of the IFN signal via the type I IFN receptor (IFNAR). A small amount of type I IFN produced early upon virus infection binds the IFNAR and activates a self-enhancing positive feedback loop, resulting in induction of large, protective amounts of IFN-α. Unexpectedly, we found robust, systemic IFN-α expression upon infection of IFNAR knockout mice with the orthomyxovirus Thogoto virus (THOV). The IFNAR-independent IFN-α production required in vivo conditions and was not achieved during in vitro infection. Using replication-incompetent THOV-derived virus-like particles, we demonstrate that IFNAR-independent type I IFN induction depends on viral polymerase activity but is largely independent of viral replication. To discover the cell type responsible for this effect, we used type I IFN reporter mice and identified CD11b(+) F4/80(+) myeloid cells within the peritoneal cavity of infected animals as the main source of IFNAR-independent type I IFN, corresponding to the particular tropism of THOV for this cell type.ImportanceType I IFNs are crucial for the survival of a host upon most viral infections, and, moreover, they shape subsequent adaptive immune responses. Production of protective amounts of type I IFN critically depends on the positive feedback amplification via the IFNAR. Unexpectedly, we observed robust IFNAR-independent type I IFN expression upon THOV infection and unraveled molecular mechanisms and determined the tissue and cell type involved. Our data indicate that the host can effectively use alternative pathways to induce type I IFN responses if the classical feedback amplification is not available. Understanding how type I IFN can be produced in large amounts independently of IFNAR-dependent enhancement will identify mechanisms which might contribute to novel therapeutic strategies to fight viral pathogens.

Project description:Background : Poxviruses have been shown to be efficient vectors for the production of protective immune responses in host species but also in on host species. Myxoma virus belongs to poxviridae family. In order to evaluate the capacity of (MYXV) as a vaccine vector in ruminants, we invistigated its interactions with bone marrow-derived dendritic cells (BM-DC). DCs are the most potent antigen-presenting cells and play a crucial role during the priming and reactivation of antigen-specific immune responses . Following infection by a pathogen, the functional changes of DC are essential since priming and polarization of the immune response depend on these changes . Therefore a better understanding of the modifications in gene expression of proinflammatory cytokines, chemokines and stimulatory molecules expression may prove useful in predicting whether or not a vaccine vector will be effective. Moreover, it may help identifying modifications for improving its efficacy. Methodology/Principal Findings: We investigated in vitro the interactions between recombinant MYXV expressing GFP protein, SG33-GFP and ovine BM-DCs. To gain a global view of the gene remodelling induced by MYXV, we infected BM-DCs from three sheep with SG33-GFP at different multiplicity of infection (MOI) (0, 1, 3) during different time (0, 3, 8 hours). We measured the expression of 15K probes in BM-DCs after each kind of conditions with ovine Agilent microarrays. Furthermore, a selected number of genes were confirmed by RT-qPCR. MYXV infection induces a strong reprogramming of the cells leading to the expression of pro-inflammatory cytokines and mobilisation of type I IFN pathways, cellular death and features associated with the activation of the adaptive immune response. Conclusion/Significance: Microarray profiling of a poxvirus-DC interaction help to delineate some interesting features of a vector candidate in ovine, and pave the way for additional improvements of a promising platform. Keywords : Myxoma virus ; bone marrow-derived dendritic cells ; transcriptome ; sheep; vaccine

Dataset Information

In vivo conversion of BM plasmacytoid DC into CD11b+ conventional DC during virus infection.

Publications

In vivo conversion of BM plasmacytoid DC into CD11b+ conventional DC during virus infection.

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