scholarly journals Dendritic Cell Responses to Early Murine Cytomegalovirus Infection

2003 ◽  
Vol 197 (7) ◽  
pp. 885-898 ◽  
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.

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

2016 ◽  
Vol 90 (10) ◽  
pp. 5108-5118 ◽  
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.

scholarly journals In Vivo Role of Dendritic Cells in a Murine Model of Pulmonary Cryptococcosis

2006 ◽  
Vol 74 (7) ◽  
pp. 3817-3824 ◽  
Author(s):  
Karen L. Wozniak ◽  
Jatin M. Vyas ◽  
Stuart M. Levitz
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Mouse Lung

ABSTRACT Dendritic cells (DC) have been shown to phagocytose and kill Cryptococcus neoformans in vitro and are believed to be important for inducing protective immunity against this organism. Exposure to C. neoformans occurs mainly by inhalation, and in this study we examined the in vivo interactions of C. neoformans with DC in the lung. Fluorescently labeled live C. neoformans and heat-killed C. neoformans were administered intranasally to C57BL/6 mice. At specific times postinoculation, mice were sacrificed, and lungs were removed. Single-cell suspensions of lung cells were prepared, stained, and analyzed by microscopy and flow cytometry. Within 2 h postinoculation, fluorescently labeled C. neoformans had been internalized by DC, macrophages, and neutrophils in the mouse lung. Additionally, lung DC from mice infected for 7 days showed increased expression of the maturation markers CD80, CD86, and major histocompatibility complex class II. Finally, ex vivo incubation of lung DC from infected mice with Cryptococcus-specific T cells resulted in increased interleukin-2 production compared to the production by DC from naïve mice, suggesting that there was antigen-specific T-cell activation. This study demonstrated that DC in the lung are capable of phagocytosing Cryptococcus in vivo and presenting antigen to C. neoformans-specific T cells ex vivo, suggesting that these cells have roles in innate and adaptive pulmonary defenses against cryptococcosis.

scholarly journals Virus-based vaccine vectors with distinct replication mechanisms differentially infect and activate dendritic cells

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Carolina Chiale ◽  
Anthony M. Marchese ◽  
Yoichi Furuya ◽  
Michael D. Robek
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Virus Replication ◽  
T Cell Activation ◽  
Viral Vectors ◽  
Cell Activation ◽  
T Cell Responses ◽  
Cell Responses ◽  
Identical Cell

AbstractThe precise mechanism by which many virus-based vectors activate immune responses remains unknown. Dendritic cells (DCs) play key roles in priming T cell responses and controlling virus replication, but their functions in generating protective immunity following vaccination with viral vectors are not always well understood. We hypothesized that highly immunogenic viral vectors with identical cell entry pathways but unique replication mechanisms differentially infect and activate DCs to promote antigen presentation and activation of distinctive antigen-specific T cell responses. To evaluate differences in replication mechanisms, we utilized a rhabdovirus vector (vesicular stomatitis virus; VSV) and an alphavirus-rhabdovirus hybrid vector (virus-like vesicles; VLV), which replicates like an alphavirus but enters the cell via the VSV glycoprotein. We found that while virus replication promotes CD8+ T cell activation by VLV, replication is absolutely required for VSV-induced responses. DC subtypes were differentially infected in vitro with VSV and VLV, and displayed differences in activation following infection that were dependent on vector replication but were independent of interferon receptor signaling. Additionally, the ability of the alphavirus-based vector to generate functional CD8+ T cells in the absence of replication relied on cDC1 cells. These results highlight the differential activation of DCs following infection with unique viral vectors and indicate potentially discrete roles of DC subtypes in activating the immune response following immunization with vectors that have distinct replication mechanisms.

Differentiation of myeloid dendritic cells into CD8α-positive dendritic cells in vivo

Blood ◽  
2000 ◽  
Vol 96 (5) ◽  
pp. 1865-1872 ◽  
Author(s):  
Miriam Merad ◽  
Lawrence Fong ◽  
Jakob Bogenberger ◽  
Edgar G. Engleman
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Wild Type Mouse ◽  
Interleukin 12 ◽  
Myeloid Dendritic Cells ◽  
Myeloid Antigens

Bone marrow-derived dendritic cells (DC) represent a family of antigen-presenting cells (APC) with varying phenotypes. For example, in mice, CD8α+ and CD8α− DC are thought to represent cells of lymphoid and myeloid origin, respectively. Langerhans cells (LC) of the epidermis are typical myeloid DC; they do not express CD8α, but they do express high levels of myeloid antigens such as CD11b and FcγR. By contrast, thymic DC, which derive from a lymphoid-related progenitor, express CD8α but only low levels of myeloid antigens. CD8α+ DC are also found in the spleen and lymph nodes (LN), but the origin of these cells has not been determined. By activating and labeling CD8α− epidermal LC in vivo, it was found that these cells expressed CD8α on migration to the draining LN. Similarly, CD8α− LC generated in vitro from a CD8 wild-type mouse and injected into the skin of a CD8αKO mouse expressed CD8α when they reached the draining LN. The results also show that CD8α+ LC are potent APC. After migration from skin, they localized in the T-cell areas of LN, secreted high levels of interleukin-12, interferon-γ, and chemokine-attracting T cells, and they induced antigen-specific T-cell activation. These results demonstrate that myeloid DC in the periphery can express CD8α when they migrate to the draining LN. CD8α expression on these DC appears to reflect a state of activation, mobilization, or both, rather than lineage.

scholarly journals Enhanced Dendritic Cell Maturation by TNF-α or Cytidine-Phosphate-Guanosine DNA Drives T Cell Activation In Vitro and Therapeutic Anti-Tumor Immune Responses In Vivo

2000 ◽  
Vol 165 (11) ◽  
pp. 6278-6286 ◽  
Author(s):  
Christoph Brunner ◽  
Julia Seiderer ◽  
Angelika Schlamp ◽  
Martin Bidlingmaier ◽  
Andreas Eigler ◽  
...  
Keyword(s):  
T Cell ◽  
Dendritic Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Dendritic Cell Maturation ◽  
Cell Maturation ◽  
Tnf Α

scholarly journals Towards Identification of the Mechanisms of Action of Parasite-Derived Peptide GK1 on the Immunogenicity of an Influenza Vaccine

2009 ◽  
Vol 16 (9) ◽  
pp. 1338-1343 ◽  
Author(s):  
René Segura-Velázquez ◽  
Gladis Fragoso ◽  
Edda Sciutto ◽  
Adelaida Sarukhan
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Influenza Vaccine ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mechanisms Of Action ◽  
The Body ◽  
Vaccine Adjuvants

ABSTRACT Previous studies have shown that the synthetic peptide GK1, derived from Taenia crassiceps cysticerci, enhances the immunogenicity of the commercial inactivated influenza vaccine Fluzone in both young and aged mice. In particular, antibody responses were much improved. Since GK1 is a peptide and is rapidly cleared from the body, it offers the possibility to improve vaccine performance without undesirable effects. This study was therefore designed to understand the mechanisms of action involved in the adjuvant properties of GK1. For this, transgenic mice expressing a T-cell receptor specific for an epitope from the influenza virus hemagglutinin (HA) protein were employed. The GK1 peptide significantly increased the in vivo proliferative response of HA-specific CD4+ T cells when it was coimmunized with the HA epitope. Dendritic cells treated in vitro with GK1 were capable of enhancing T-cell activation. Furthermore, in synergy with lipopolysaccharide, GK1 enhanced the expression of major histocompatibility complex class II and costimulatory molecules of dendritic cells and promoted the secretion of proinflammatory cytokines and chemokines upon antigen-driven T-cell interaction. These data provide important insights into the mechanism that underlies the GK1 adjuvant capacity observed previously and underline the feasibility of using the transgenic mouse model described herein as a tool for investigation of the modes of action of different influenza vaccine adjuvants.

scholarly journals Induction of Antigen-Specific T-Cell Responses through Dendritic Cell Vaccination in AML: Results of a Phase I/II Trial and Ex Vivo Enhancement By Checkpoint Blockade

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 764-764 ◽  
Author(s):  
Felix S. Lichtenegger ◽  
Katrin Deiser ◽  
Maurine Rothe ◽  
Frauke M. Schnorfeil ◽  
Christina Krupka ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Phase I ◽  
T Cell Activation ◽  
Cell Activation ◽  
Next Generation ◽  
Cell Responses ◽  
Ifn Γ

Abstract Postremission therapy is critical for successful elimination of minimal residual disease (MRD) in acute myeloid leukemia (AML). Innovative treatment options are needed for patients that are not eligible for allogeneic stem cell transplantation. As the intrinsic immune response against leukemia-associated antigens (LAAs) is generally low, the clinical application of checkpoint inhibitors as monotherapy is less promising in AML compared to other hemato-oncological diseases. Therapeutic vaccination with autologous dendritic cells (DCs) loaded with LAAs is a promising treatment strategy to induce anti-leukemic immune responses. We have conducted a phase I/II proof-of-concept study using monocyte-derived next-generation DCs as postremission therapy of AML patients with a non-favorable risk profile in CR/CRi after intensive induction therapy (NCT01734304). These DCs are generated using a GMP-compliant 3-day protocol including a TLR7/8 agonist, loaded with RNA encoding the LAAs WT1 and PRAME as well as CMVpp65 as adjuvant/surrogate antigen, and are applied intradermally up to 10 times within 26 weeks. The primary endpoint of the trial is feasibility and safety of the vaccination. Secondary endpoints are immunological responses and disease control. After the safety and toxicity profile was evaluated within phase I (n=6), the patient cohort was expanded to a total of 13 patients. DCs of sufficient number and quality could be generated from leukapheresis in 11/12 cases. DCs exhibited an immune-stimulatory profile based on high costimulatory molecule expression, IL-12p70 secretion, migration towards a chemokine gradient and processing and presentation of antigen. In 9/9 patients that are currently evaluable, we observed delayed-type hypersensitivity (DTH) responses at the vaccination site, but no grade III/IV toxicities. TCR repertoire analysis by next-generation sequencing revealed an enrichment of particular clonotypes at DTH sites. In the peripheral blood, we detected vaccination-specific T cell responses by multimer staining and by ELISPOT analysis: 7/7 patients showed responses to CMVpp65, including both boosting of pre-existing T cells in CMV+ patients and induction of a primary T cell response in CMV- patients. 2/7 patients exhibited responses to PRAME and WT each. 7/10 vaccinated patients are still alive, and 5/10 are in CR, with an observation period of up to 840 days. In vitro, DC-activated T cells showed an upregulation of PD-1 and LAG-3, while the DCs expressed the respective ligands PD-L1 and HLA-DR. Therefore, we studied the capacity of checkpoint blocking antibodies to further enhance T-cell activation by DCs. We found that blockade of PD-1 and particularly of LAG-3 was highly effective in enhancing both IFN-γ secretion and proliferation of T cells. Both pathways seem to target different T-cell subsets, as PD-1 blockade resulted in increased IFN-γ secretion by TN- and TEM-subsets, while blockade of LAG-3 significantly affected TN- and TCM-subsets. We conclude that vaccination with next-generation LAA-expressing DCs in AML is feasible, safe, and induces anti-leukemic immune responses in vivo. Our in vitro data supports the hypothesis that T-cell activation by means of the vaccine could be further enhanced by blocking PD-1 and/or LAG-3. Disclosures Subklewe: AMGEN Research Munich: Research Funding.

Bone marrow microenvironment controls the in vivo differentiation of murine dendritic cells into osteoclasts

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 5074-5083 ◽  
Author(s):  
Abdelilah Wakkach ◽  
Anna Mansour ◽  
Romain Dacquin ◽  
Emmanuel Coste ◽  
Pierre Jurdic ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Bone Cells ◽  
Activated T Cells

Abstract Finding that activated T cells control osteoclast (OCL) differentiation has revealed the importance of the interactions between immune and bone cells. Dendritic cells (DCs) are responsible for T-cell activation and share common precursors with OCLs. Here we show that DCs participate in bone resorption more directly than simply through T-cell activation. We show that, among the splenic DC subsets, the conventional DCs have the higher osteoclastogenic potential in vitro. We demonstrate that conventional DCs differentiate into functional OCLs in vivo when injected into osteopetrotic oc/oc mice defective in OCL resorptive function. Moreover, this differentiation involves the presence of activated CD4+ T cells controlling a high RANK-L expression by bone marrow stromal cells. Our results open new insights in the differentiation of OCLs and DCs and offer new basis for analyzing the relations between bone and immune systems.

Sign in / Sign up

Export Citation Format

Share Document