Murine plasmacytoid dendritic cells induce effector/memory CD8+ T-cell responses in vivo after viral stimulation.

Unité de Biologie des Régulations Immunitaires, Institut National de la Santé et de la Recherche Médicale, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris cedex 15, France.
Blood (Impact Factor: 9.78). 10/2004; 104(6):1808-15. DOI: 10.1182/blood-2004-02-0426
Source: PubMed

ABSTRACT Like their human counterparts, mouse plasmacytoid dendritic cells (pDCs) play a central role in innate immunity against viral infections, but their capacity to prime T cells in vivo remains unknown. We show here that virus-activated pDCs differentiate into antigen-presenting cells able to induce effector/memory CD8(+) T-cell responses in vivo against both epitopic peptides and endogenous antigen, whereas pDCs activated by synthetic oligodeoxynucleotides containing unmethylated cytosine-guanine motifs (CpG) acquire only the ability to recall antigen-experienced T-cell responses. We also show that immature pDCs are unable to induce effector or regulatory CD8(+) T-cell responses. Thus, murine pDCs take part in both innate and adaptive immune responses by directly priming naive CD8(+) T cells during viral infection.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: jimmun published online 31 October 2014 J Immunol Material Supplementary 8.DCSupplemental.html Subscriptions is online at: The Journal of Immunology Information about subscribing to Permissions http: Tolerance induction by dendritic cells (DCs) is, in part, mediated by the activation of regulatory T cells (Tregs). We have previously shown in vitro that human DCs treated with glucocorticoids (GCs), IL-10, or TGF-b upregulate the GC-Induced Leucine Zipper protein (GILZ). GILZ overexpression promotes DC differentiation into regulatory cells that generate IL-10– producing Ag-specific Tregs. To investigate whether these observations extend in vivo, we have generated CD11c-GILZ hi trans-genic mice. DCs from these mice constitutively overexpress GILZ to levels observed in GC-treated wild-type DCs. In this article, we establish that GILZ hi DCs display an accumulation of Foxp3 + Tregs in the spleens of young CD11c-GILZ hi mice. In addition, we show that GILZ hi DCs strongly increase the Treg pool in central and peripheral lymphoid organs of aged animals. Upon adoptive transfer to wild-type recipient mice, OVA-loaded GILZ hi bone marrow–derived DCs induce a reduced activation and proliferation of OVA-specific T cells as compared with control bone marrow–derived DCs, associated with an expansion of thymus-derived CD25 + Foxp3 + CD4 T cells. Transferred OVA-loaded GILZ hi DCs produce significantly higher levels of IL-10 and express reduced levels of MHC class II molecules as compared with OVA-loaded control DCs, emphasizing the regulatory phenotype of GILZ hi DCs in vivo. Thus, our work demonstrates in vivo that the GILZ overexpression alone is sufficient to promote a tolerogenic mode of function in DCs.
    10/2014; 193:0-0.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Dendritic cell (DC)-based immunotherapy employs the patients' immune system to fight neoplastic lesions spread over the entire body. This makes it an important therapy option for patients suffering from metastatic melanoma, which is often resistant to chemotherapy. However, conventional cellular vaccination approaches, based on monocyte-derived DCs (moDCs), only achieved modest response rates despite continued optimization of various vaccination parameters. In addition, the generation of moDCs requires extensive ex vivo culturing conceivably hampering the immunogenicity of the vaccine. Recent studies, thus, focused on vaccines that make use of primary DCs. Though rare in the blood, these naturally circulating DCs can be readily isolated and activated thereby circumventing lengthy ex vivo culture periods. The first clinical trials not only showed increased survival rates but also the induction of diversified anti-cancer immune responses. Upcoming treatment paradigms aim to include several primary DC subsets in a single vaccine as pre-clinical studies identified synergistic effects between various antigen-presenting cells.
    Frontiers in Immunology 01/2014; 5:165.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Plasmacytoid dendritic cells (pDCs) are considered to be the principal type-I IFN (IFN-I) source in response to viruses, whereas the contribution of conventional DCs (cDCs) has been underestimated because, on a per-cell basis, they are not considered professional IFN-I-producing cells. We have investigated their respective roles in the IFN-I response required for CTL activation. Using a nonreplicative virus, baculovirus, we show that despite the high IFN-I-producing abilities of pDCs, in vivo cDCs but not pDCs are the pivotal IFN-I producers upon viral injection, as demonstrated by selective pDC or cDC depletion. The pathway involved in the virus-triggered IFN-I response is dependent on TLR9/MyD88 in pDCs and on stimulator of IFN genes (STING) in cDCs. Importantly, STING is the key molecule for the systemic baculovirus-induced IFN-I response required for CTL priming. The supremacy of cDCs over pDCs in fostering the IFN-I response required for CTL activation was also verified in the lymphocytic choriomeningitis virus model, in which IFN-β promoter stimulator 1 plays the role of STING. However, when the TLR-independent virus-triggered IFN-I production is impaired, the pDC-induced IFNs-I have a primary impact on CTL activation, as shown by the detrimental effect of pDC depletion and IFN-I signaling blockade on the residual lymphocytic choriomeningitis virus-triggered CTL response detected in IFN-β promoter stimulator 1(-/-) mice. Our findings reveal that cDCs play a major role in the TLR-independent virus-triggered IFN-I production required for CTL priming, whereas pDC-induced IFNs-I are dispensable but become relevant when the TLR-independent IFN-I response is impaired.
    The Journal of Immunology 06/2014; · 5.36 Impact Factor

Full-text (2 Sources)

Available from
May 22, 2014