CD40-deficient dendritic cells producing interleukin-10, but not interleukin-12, induce T-cell hyporesponsiveness in vitro and prevent acute allograft rejection

Chemokines provide signals for activation and recruitment of effector cells into sites of inflammation, acting via specific G protein–coupled receptors. However, in vitro data demonstrating the presence of multiple ligands for a given chemokine receptor, and often multiple receptors for a given chemokine, have led to concerns of biologic redundancy. Here we show that acute cardiac allograft rejection is accompanied by progressive intragraft production of the chemokines interferon (IFN)-γ–inducible protein of 10 kD (IP-10), monokine induced by IFN-γ (Mig), and IFN-inducible T cell α chemoattractant (I-TAC), and by infiltration of activated T cells bearing the corresponding chemokine receptor, CXCR3. We used three in vivo models to demonstrate a role for CXCR3 in the development of transplant rejection. First, CXCR3-deficient (CXCR3−/−) mice showed profound resistance to development of acute allograft rejection. Second, CXCR3−/− allograft recipients treated with a brief, subtherapeutic course of cyclosporin A maintained their allografts permanently and without evidence of chronic rejection. Third, CXCR+/+ mice treated with an anti-CXCR3 monoclonal antibody showed prolongation of allograft survival, even if begun after the onset of rejection. Taken in conjunction with our findings of CXCR3 expression in rejecting human cardiac allografts, we conclude that CXCR3 plays a key role in T cell activation, recruitment, and allograft destruction.

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A subset of human monocyte-derived dendritic cells expresses high levels of interleukin-12 in response to combined CD40 ligand and interferon-γ treatment

Blood ◽

10.1182/blood.v96.10.3499 ◽

2000 ◽

Vol 96 (10) ◽

pp. 3499-3504 ◽

Cited By ~ 100

Author(s):

Paul J. Mosca ◽

Amy C. Hobeika ◽

Timothy M. Clay ◽

Smita K. Nair ◽

Elaine K. Thomas ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Human Monocyte ◽

Cd40 Ligand ◽

Cell Surface Expression ◽

Interleukin 12 ◽

Cytokine Detection

Abstract Dendritic cells (DCs) may arise from multiple lineages and progress through a series of intermediate stages until fully mature, at which time they are capable of optimal antigen presentation and T-cell activation. High cell surface expression of CD83 is presumed to correlate with full maturation of DCs, and a number of agents have been shown to increase CD83 expression on DCs. We hypothesized that interleukin 12 (IL-12) expression would be a more accurate marker of functionally mature DCs capable of activating antigen-specific T cells. We used combinations of signaling through CD40, using CD40 ligand trimer (CD40L), and interferon gamma to demonstrate that CD83 expression is necessary but not sufficient for optimal production of IL-12 by DCs. Phenotypically mature DCs could be induced to produce high levels of IL-12 p70 only when provided 2 simultaneous stimulatory signals. By intracellular cytokine detection, we determined that only a subset of cells that express high levels of CD80 and CD83 generate large amounts of IL-12. DCs matured with both signals are superior to DCs stimulated with the individual agents in activating antigen-specific T cell in vitro. These findings have important implications regarding the identification, characterization, and clinical application of functionally mature DCs.

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

Blood ◽

10.1182/blood.v96.5.1865.h8001865_1865_1872 ◽

2000 ◽

Vol 96 (5) ◽

pp. 1865-1872 ◽

Cited By ~ 2

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.

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Enhancing the immunostimulatory function of dendritic cells by transfection with mRNA encoding OX40 ligand

Blood ◽

10.1182/blood-2004-10-3944 ◽

2005 ◽

Vol 105 (8) ◽

pp. 3206-3213 ◽

Cited By ~ 77

Author(s):

Jens Dannull ◽

Smita Nair ◽

Zhen Su ◽

David Boczkowski ◽

Christian DeBeck ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

T Cell Responses ◽

Human Monocyte ◽

Interleukin 12 ◽

T Helper ◽

Cell Responses ◽

Mrna Transfection

Abstract The objective of this study was to investigate whether the immunostimulatory properties of human monocyte-derived dendritic cells (DCs) could be enhanced by triggering OX40/OX40L signaling. Since monocyte-derived DCs possess only low-cell surface levels of OX40L in the absence of CD40 signaling, OX40L was expressed by transfection of DCs with the corresponding mRNA. We show that OX40L mRNA transfection effectively enhanced the immunostimulatory function of DCs at multiple levels: OX40L mRNA transfection augmented allogeneic and HLA class II epitope-specific CD4+ T-cell responses, improved the stimulation of antigen-specific cytotoxic T lymphocytes (CTLs) in vitro without interfering with the prostaglandin E2 (PGE2)–mediated migratory function of the DCs, and facilitated interleukin 12 p70 (IL-12p70)–independent T helper type 1 (Th1) polarization of naive CD4+ T-helper cells. Furthermore, vaccination of tumor-bearing mice using OX40L mRNA–cotransfected DCs resulted in significant enhancement of therapeutic antitumor immunity due to in vivo priming of Th1-type T-cell responses. Our data suggest that transfection of DCs with OX40L mRNA may represent a promising strategy that could be applied in clinical immunotherapy protocols, while circumventing the current unavailability of reagents facilitating OX40 ligation.

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Ovarian Cancer Cells Induce Peripheral Mature Dendritic Cells to Differentiate Into Macrophagelike Cells In Vitro

International Journal of Gynecological Cancer ◽

10.1111/igc.0b013e3181bb70c6 ◽

2009 ◽

Vol 19 (9) ◽

pp. 1487-1493 ◽

Cited By ~ 12

Author(s):

Fangxue Chen ◽

Meng Hou ◽

Feng Ye ◽

Weiguo Lv ◽

Xing Xie

Keyword(s):

Ovarian Cancer ◽

Dendritic Cells ◽

T Cell ◽

Cancer Cells ◽

Fluorescein Isothiocyanate ◽

Interleukin 10 ◽

Interleukin 4 ◽

Ovarian Cancer Cells ◽

Macrophage Colony

Aims:Precursors of dendritic cells (DCs) are able to differentiate into macrophages induced by some tumor-associated molecules; however, whether peripheral mature DCs could differentiate into macrophages remains unknown. This study was designed to find out whether ovarian cancer cells could induce peripheral mature DCs to differentiate into macrophages.Main Methods:Mature DCs were cultured from monocytes with granulocyte-macrophage colony-stimulating factor and interleukin 4 (IL-4) for 6 days and lipopolysaccharide for another 24 hours and then were cocultured for 48 hours with ovarian cancer ascites or cell-free supernatants of SKOV3 and CAOV3 cell lines. In some experiments, mature DCs were cultured in the absence or presence of IL-10 or leukemia inhibitory factor (LIF) for the same time. In neutralization experiments, neutralizing monoclonal antibodies to IL-10 or LIF were added to the cultures. Cell phenotypes and phagocytosis were analyzed using flow cytometry; allogeneic T-cell proliferation assay was used to examine stimulatory activity of cells.Results and Conclusions:Mature DCs cocultured with ovarian cancer ascites or supernatants of SKOV3 and CAOV3 differentiated into a group of macrophagelike cells that exhibited increased expression of surface marker CD14+CD1a−, decreased expression of CD83, poorer T-cell costimulatory properties, and greater endocytosis of fluorescein isothiocyanate-dextran in vitro. Interleukin 10 but not LIF mediated this differentiation pathway.

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Both exogenous and endogenous interleukin-10 affects the maturation of bone-marrow-derived dendritic cells in vitro and strongly influences T-cell priming in vivo

Immunology ◽

10.1046/j.1365-2567.2002.01529.x ◽

2002 ◽

Vol 107 (4) ◽

pp. 489-499 ◽

Cited By ~ 39

Author(s):

Claus Haase ◽

Trine N. Jorgensen ◽

Birgitte K. Michelsen

Keyword(s):

Bone Marrow ◽

Dendritic Cells ◽

T Cell ◽

Interleukin 10 ◽

T Cell Priming

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The Selenoprotein MsrB1 Instructs Dendritic Cells to Induce T-Helper 1 Immune Responses

Antioxidants ◽

10.3390/antiox9101021 ◽

2020 ◽

Vol 9 (10) ◽

pp. 1021

Author(s):

Ho-Jae Lee ◽

Joon Seok Park ◽

Hyun Jung Yoo ◽

Hae Min Lee ◽

Byung Cheon Lee ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Immune Responses ◽

Therapeutic Potential ◽

Methionine Sulfoxide Reductase ◽

Interleukin 12 ◽

T Helper ◽

T Helper 1

Immune activation associates with the intracellular generation of reactive oxygen species (ROS). To elicit effective immune responses, ROS levels must be balanced. Emerging evidence shows that ROS-mediated signal transduction can be regulated by selenoproteins such as methionine sulfoxide reductase B1 (MsrB1). However, how the selenoprotein shapes immunity remains poorly understood. Here, we demonstrated that MsrB1 plays a crucial role in the ability of dendritic cells (DCs) to provide the antigen presentation and costimulation that are needed for cluster of differentiation antigen four (CD4) T-cell priming in mice. We found that MsrB1 regulated signal transducer and activator of transcription-6 (STAT6) phosphorylation in DCs. Moreover, both in vitro and in vivo, MsrB1 potentiated the lipopolysaccharide (LPS)-induced Interleukin-12 (IL-12) production by DCs and drove T-helper 1 (Th1) differentiation after immunization. We propose that MsrB1 activates the STAT6 pathway in DCs, thereby inducing the DC maturation and IL-12 production that promotes Th1 differentiation. Additionally, we showed that MsrB1 promoted follicular helper T-cell (Tfh) differentiation when mice were immunized with sheep red blood cells. This study unveils as yet unappreciated roles of the MsrB1 selenoprotein in the innate control of adaptive immunity. Targeting MsrB1 may have therapeutic potential in terms of controlling immune reactions.

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

Blood ◽

10.1182/blood.v96.5.1865 ◽

2000 ◽

Vol 96 (5) ◽

pp. 1865-1872 ◽

Cited By ~ 78

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

Abstract 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.

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Differential Interaction of Dendritic Cells with Rickettsia conorii: Impact on Host Susceptibility to Murine Spotted Fever Rickettsiosis

Infection and Immunity ◽

10.1128/iai.00007-07 ◽

2007 ◽

Vol 75 (6) ◽

pp. 3112-3123 ◽

Cited By ~ 43

Author(s):

Rong Fang ◽

Nahed Ismail ◽

Lynn Soong ◽

Vsevolod L. Popov ◽

Ted Whitworth ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

T Cell Activation ◽

Spotted Fever ◽

Interleukin 12 ◽

Mouse Strains ◽

Rickettsia Conorii ◽

Spotted Fever Group ◽

C3h Mice

ABSTRACT Spotted fever group rickettsioses are emerging and reemerging infectious diseases, some of which are life-threatening. In order to understand how dendritic cells (DCs) contribute to the host resistance or susceptibility to rickettsial diseases, we first characterized the in vitro interaction of rickettsiae with bone marrow-derived DCs (BMDCs) from resistant C57BL/6 (B6) and susceptible C3H/HeN (C3H) mice. In contrast to the exclusively cytosolic localization within endothelial cells, rickettsiae efficiently entered and localized in both phagosomes and cytosol of BMDCs from both mouse strains. Rickettsia conorii-infected BMDCs from resistant mice harbored higher bacterial loads compared to C3H mice. R. conorii infection induced maturation of BMDCs from both mouse strains as judged by upregulated expression of classical major histocompatibility complex (MHC) and costimulatory molecules. Compared to C3H counterparts, B6 BMDCs exhibited higher expression levels of MHC class II and higher interleukin-12 (IL-12) p40 production upon rickettsial infection and were more potent in priming naïve CD4+ T cells to produce gamma interferon. In vitro DC infection and T-cell priming studies suggested a delayed CD4+ T-cell activation and suppressed Th1/Th2 cell development in C3H mice. The suppressive CD4+ T-cell responses seen in C3H mice were associated with a high frequency of Foxp3+ T regulatory cells promoted by syngeneic R. conorii-infected BMDCs in the presence of IL-2. These data suggest that rickettsiae can target DCs to stimulate a protective type 1 response in resistant hosts but suppressive adaptive immunity in susceptible hosts.

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