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1.  INTERFERON-PRODUCING KILLER DENDRITIC CELLS ARE ANTIGEN PRESENTING CELLS ENDOWED WITH T CELL CROSS-PRIMING CAPACITY 
Cancer research  2009;69(16):6607-6614.
Interferon-producing killer dendritic cells (IKDC) represent a recently discovered cell type in the immune system that possesses a number of functions contributing to innate and adaptive immunity, including production of type 1 and 2 IFNs, IL-12, natural killing, and ultimately antigen presentation to naïve T-cells. Here, we compared in vitro and in vivo responses of mouse IKDC, conventional dendritic cells and natural killer cells to murine cytomegalovirus infection and found distinct functions among these cell subsets. Upon recognition of infected fibroblasts, IKDC, as well as NK, produced high level of IFN-γ, but unlike NK, IKDC simultaneously produced IL-12p40 and upregulated MHC class II and costimulatory molecules. Using MHC-II molecule expression as a phenotypic marker to distinguish activated IKDC from activated NK, we further demonstrated that highly purified MHC-II+ IKDC but not NK, cross-present MHC class I-restricted antigens derived from MCMV-infected targets to CD8+ T-cells in vitro and in vivo. Our findings emphasize the unique nature of IKDC as a killer antigen presenting cell directly linking innate and adaptive immunity.
doi:10.1158/0008-5472.CAN-09-0508
PMCID: PMC2761009  PMID: 19679552
IKDC and cross-presentation; Dendritic cell; Antigen presentation; Natural killer
2.  Putative IKDCs are functionally and developmentally similar to natural killer cells, but not to dendritic cells 
The Journal of Experimental Medicine  2007;204(11):2579-2590.
Interferon-producing killer dendritic cells (IKDCs) have been described as possessing the lytic potential of NK cells and the antigen-presenting capacity of dendritic cells (DCs). In this study, we examine the lytic function and antigen-presenting capacity of mouse spleen IKDCs, including those found in DC preparations. IKDCs efficiently killed NK cell targets, without requiring additional activation stimuli. However, in our hands, when exposed to protein antigen or to MHC class II peptide, IKDCs induced little or no T cell proliferation relative to conventional DCs or plasmacytoid DCs, either before or after activation with CpG, or in several disease models. Certain developmental features indicated that IKDCs resembled NK cells more than DCs. IKDCs, like NK cells, did not express the transcription factor PU.1 and were absent from recombinase activating gene-2–null, common γ-chain–null (Rag2−/−Il2rg−/−) mice. When cultured with IL-15 and -18, IKDCs proliferated extensively, like NK cells. Under these conditions, a proportion of expanded IKDCs and NK cells expressed high levels of surface MHC class II. However, even such MHC class II+ IKDCs and NK cells induced poor T cell proliferative responses compared with DCs. Thus, IKDCs resemble NK cells functionally, and neither cell type could be induced to be effective antigen-presenting cells.
doi:10.1084/jem.20071351
PMCID: PMC2118479  PMID: 17923506
3.  Genetic characterization of interferon-producing killer dendritic cells 
The combined phenotypic expression of CD11clow B220+ CD122+ DX5+ has been used to define a novel cell type, termed interferon-producing killer dendritic cells (IKDC). IKDC readily produce IFN-γ and demonstrate spontaneous cytotoxic activity towards tumors, suggesting that a modulation of IKDC number may be beneficial in cancer treatment. We examined various mouse strains and found that IKDC number was highly variable between the different strains. A linkage analysis associated the distal arm of chromosome 7 with variations in IKDC number. The genetic contribution of chromosome 7 to the regulation of IKDC number was confirmed through the use of congenic mice. We further demonstrate that IKDC proportion is regulated by intrinsic hematopoietic factors. We discuss the role of various candidate genes in the regulation of this newly described cell type and its implication in therapy.
doi:10.4049/jimmunol.0803969
PMCID: PMC2697453  PMID: 19380763
Dendritic Cells; Natural Killer Cells; Tumor Immunity
4.  SUBVERSION OF PULMONARY DENDRITIC CELL FUNCTION BY PARAMYXOVIRUS INFECTIONS1 
Lower respiratory tract infections caused by the paramyxoviruses human metapneumovirus (hMPV) and respiratory syncytial virus (RSV) are characterized by short-lasting virus-specific immunity and often long term airway morbidity, both of which may be the result of alterations in the antigen presenting function of the lung which follow these infections. In this study, we investigated whether hMPV and RSV experimental infections alter the phenotype and function of dendritic cells (DC) subsets which are recruited to the lung. Characterization of lung DC trafficking demonstrated a differential recruitment of plasmacytoid DC (pDC), conventional DC (cDC) and interferon-producing killer DC (IKDC) to the lung and draining lymph nodes after hMPV and RSV infection. In vitro infection of lung DC indicated that in pDC, production of IFN-α, TNF-α, and CCL5 was induced only by hMPV while CCL3 and CCL4 were induced by both viruses. In cDC, a similar repertoire of cytokines was induced by hMPV and RSV, except for IFN-β, which was not induced by RSV. The function of lung pDC was altered following hMPV or RSV infection in vivo, as we demonstrated a reduced capacity of lung pDC to produce IFN-α as well as other cytokines including IL-6, TNF-α, CCL2, CCL3 and CCL4 in response to TLR9 agonist. Moreover, we observed an impaired capacity of cDC from infected mice to present Ag to CD4+ T cells, an effect that lasted beyond the acute phase of infection. Our findings suggest that acute paramyxovirus infections can alter the long term immune function of pulmonary DC.
doi:10.4049/jimmunol.0802262
PMCID: PMC2865244  PMID: 19234204
Dendritic cells; Lung; Viral; Cytokines; Cell trafficking
5.  Tolerogen-induced interferon-producing killer dendritic cells (IKDCs) protect against EAE 
Journal of autoimmunity  2011;37(4):328-341.
Natural killer (NK) cells and dendritic cells (DCs) have been shown to link the innate and adaptive immune systems. Likewise, a new innate cell subset, interferon-producing killer DCs (IKDCs), shares phenotypic and functional characteristics with both DCs and NK cells. Here, we show IKDCs play an essential role in the resolution of experimental autoimmune encephalomyelitis (EAE) upon treatment with the tolerizing agent, myelin oligodendrocyte glycoprotein (MOG), genetically fused to reovirus protein σ1 (termed MOG-pσ1). Activated IKDCs were recruited subsequent MOG-pσ1 treatment of EAE, and disease resolution was abated upon NK1.1 cell depletion. These IKDCs were able to kill activated CD4+ T cells and mature dendritic DCs, thus, contributing to EAE remission. In addition, IKDCs were responsible for MOG-pσ1-mediated MOG-specific regulatory T cell recruitment to the CNS. The IKDCs induced by MOG-pσ1 expressed elevated levels of HVEM for interactions with cognate ligand-positive cells: LIGHT+ NK and Teff cells and BTLA+ B cells. Further characterization revealed these activated IKDCs being MHC class IIhigh, and upon their adoptive transfer (CD11c+NK1.1+MHC class IIhigh), IKDCs, but not CD11c+NK1.1+MHC class IIintermediate/low (unactivated) cells, conferred protection against EAE. These activated IKDCs showed enhanced CD107a, PD-L1, and granzyme B expression and could present OVA, unlike unactivated IKDCs. Thus, these results demonstrate the interventional potency induced HVEM+ IKDCs to resolve autoimmune disease.
doi:10.1016/j.jaut.2011.09.005
PMCID: PMC3237120  PMID: 22018711
EAE; tolerance; Treg cells; IKDC; HVEM
6.  CD11cloB220+ interferon-producing killer dendritic cells are activated natural killer cells 
The Journal of Experimental Medicine  2007;204(11):2569-2578.
Interferon-producing killer dendritic cells (IKDCs) are a recently described subset of CD11cloB220+ cells that share phenotypic and functional properties of DCs and natural killer (NK) cells (Chan, C.W., E. Crafton, H.N. Fan, J. Flook, K. Yoshimura, M. Skarica, D. Brockstedt, T.W. Dubensky, M.F. Stins, L.L. Lanier, et al. 2006. Nat. Med. 12:207–213; Taieb, J., N. Chaput, C. Menard, L. Apetoh, E. Ullrich, M. Bonmort, M. Pequignot, N. Casares, M. Terme, C. Flament, et al. 2006. Nat. Med. 12:214–219). IKDC development appears unusual in that cytokines using the interleukin (IL)-2 receptor β (IL-2Rβ) chain but not those using the common γ chain (γc) are necessary for their generation. By directly comparing Rag2−/−γc−/y, Rag2−/−IL-2Rβ−/−, Rag2−/−IL-15−/−, and Rag2−/−IL-2−/− mice, we demonstrate that IKDC development parallels NK cell development in its strict IL-15 dependence. Moreover, IKDCs uniformly express NK-specific Ncr-1 transcripts (encoding NKp46), whereas NKp46+ cells are absent in Ncr1gfp/+γc−/y mice. Distinguishing features of IKDCs (CD11cloB220+MHC-II+) were carefully examined on developing NK cells in the bone marrow and on peripheral NK cells. As B220 expression was heterogeneous, defining B220lo versus B220hi NK1.1+ NK cells could be considered as arbitrary, and few phenotypic differences were noted between NK1.1+ NK cells bearing different levels of B220. CD11c expression did not correlate with B220 or major histocompatibility complex (MHC) class II (MHC-II) expression, and most MHC-II+ NK1.1+ cells did not express B220 and were thus not IKDCs. Finally, CD11c, MHC-II, and B220 levels were up-regulated on NK1.1+ cells upon activation in vitro or in vivo in a proliferation-dependent fashion. Our data suggest that the majority of CD11cloB220+ “IKDC-like” cells represent activated NK cells.
doi:10.1084/jem.20071451
PMCID: PMC2118499  PMID: 17923507
7.  Revisiting the Prominent Anti-Tumoral Potential of Pre-mNK Cells 
Interferon-producing killer dendritic cells (IKDC) were first described for their outstanding anti-tumoral properties. The “IKDC” terminology implied the description of a novel DC subset and initiated a debate on their cellular lineage origin. This debate shifted the focus away from their notable anti-tumoral potential. IKDC were recently redefined as precursors to mature NK (mNK) cells and consequently renamed pre-mNK cells. Importantly, a putative human equivalent of pre-mNK cells was recently associated with improved disease outcome in cancer patients. It is thus timely to revisit the functional attributes as well as the therapeutic potential of pre-mNK cells in line with their newly defined NK-cell precursor function.
doi:10.3389/fimmu.2013.00446
PMCID: PMC3858890  PMID: 24376447
natural killer cells; cellular differentiation; pre-mNK cells; anti-tumoral activity; human; mouse
8.  IL-12 in conjunction with dendritic cells enhances antiviral CD8+ CTL responses in vitro. 
Journal of Clinical Investigation  1996;98(3):715-722.
CD8+ cytolytic T lymphocytes (CTLs) are important mediators for resistance to infections and malignant diseases. IL-12 enhances proliferative and cytolytic responses by killer cells, but its function in the generation of human antiviral CD8+ T cell responses has not been defined. We therefore evaluated the role of IL-12 in the generation of CTLs to influenza-infected dendritic cells. IL-12 was not detectable in supernatants of infected-dendritic cells, or during CTL generation. Furthermore, anti-IL-12 antibody did not block CTL generation. However, exogenous IL-12 (30-300 pg/ml) enhanced CD8+ T cell proliferative and cytolytic responses. The effect was greatest in individuals with weak reactivity to influenza virus or at antigen-presenting cell (APC):T cell ratios of 1:100 or less. IL-12 augmented interferon-gamma production during CTL generation. The CTL enhancing effects of the cytokine, however, could not be blocked by neutralizing anti-interferon-gamma antibody. Together with IL-12, antigen-pulsed dendritic cells may be a useful approach for boosting CTL responses against infectious agents and malignancies.
PMCID: PMC507481  PMID: 8698863
9.  Unique Type I Interferon Responses Determine the Functional Fate of Migratory Lung Dendritic Cells during Influenza Virus Infection 
PLoS Pathogens  2011;7(11):e1002345.
Migratory lung dendritic cells (DCs) transport viral antigen from the lungs to the draining mediastinal lymph nodes (MLNs) during influenza virus infection to initiate the adaptive immune response. Two major migratory DC subsets, CD103+ DCs and CD11bhigh DCs participate in this function and it is not clear if these antigen presenting cell (APC) populations become directly infected and if so whether their activity is influenced by the infection. In these experiments we show that both subpopulations can become infected and migrate to the draining MLN but a difference in their response to type I interferon (I-IFN) signaling dictates the capacity of the virus to replicate. CD103+ DCs allow the virus to replicate to significantly higher levels than do the CD11bhigh DCs, and they release infectious virus in the MLNs and when cultured ex-vivo. Virus replication in CD11bhigh DCs is inhibited by I-IFNs, since ablation of the I-IFN receptor (IFNAR) signaling permits virus to replicate vigorously and productively in this subset. Interestingly, CD103+ DCs are less sensitive to I-IFNs upregulating interferon-induced genes to a lesser extent than CD11bhigh DCs. The attenuated IFNAR signaling by CD103+ DCs correlates with their described superior antigen presentation capacity for naïve CD8+ T cells when compared to CD11bhigh DCs. Indeed ablation of IFNAR signaling equalizes the competency of the antigen presenting function for the two subpopulations. Thus, antigen presentation by lung DCs is proportional to virus replication and this is tightly constrained by I-IFN. The “interferon-resistant” CD103+ DCs may have evolved to ensure the presentation of viral antigens to T cells in I-IFN rich environments. Conversely, this trait may be exploitable by viral pathogens as a mechanism for systemic dissemination.
Author Summary
Migratory lung dendritic cells (DCs) control the initiation of the adaptive immune responses to influenza virus by expanding virus-specific T cells in draining lymph nodes (MLNs) that will subsequently clear the pathogen from the respiratory tract. Here we demonstrate that both subsets of lung DCs, CD103+ DCs and CD11bhigh DCs become infected by influenza virus in vivo and migrate to the MLNs, but only CD103+ DCs support productive virus replication. Enhanced virus replication in CD103+ DCs compared to CD11bhigh DCs was responsible for their superior antigen presentation efficacy for naïve CD8+ T cells and originated from a difference in sensitivity of the two DC populations to type I interferon (I-IFN). These data show that in contrast to most other immune cell types, DCs can become productively infected with influenza virus and I-IFN operates as a master regulator controlling which DC subset will present antigen during a viral infection. A deeper understanding of basic innate and adaptive immune response mechanisms regulated by I-FN may lead to the development of cutting edge therapies and improve vaccine efficacy against influenza and other viruses.
doi:10.1371/journal.ppat.1002345
PMCID: PMC3207893  PMID: 22072965
10.  Development and function of murine B220+CD11c+NK1.1+ cells identify them as a subset of NK cells 
The Journal of Experimental Medicine  2007;204(11):2561-2568.
Lymphoid organs contain a B220+CD11c+NK1.1+ cell population that was recently characterized as a novel dendritic cell (DC) subset that functionally overlaps with natural killer (NK) cells and plasmacytoid DCs (PDCs). Using Siglec-H and NK1.1 markers, we unambiguously dissected B220+CD11c+ cells and found that PDCs are the only professional interferon (IFN)-α–producing cells within this heterogeneous population. In contrast, B220+CD11c+NK1.1+ cells are a discrete NK cell subset capable of producing higher levels of IFN-γ than conventional NK cells. Unlike DCs, only a minute fraction of B220+CD11c+NK1.1+ cells in the spleen expressed major histocompatibility complex class II ex vivo or after stimulation with CpG. Consistent with being a NK cell subset, B220+CD11c+NK1.1+ cells depended primarily on interleukin 15 and common cytokine receptor γ chain signaling for their development. In terms of function, expression of distinctive cell surface receptors, and location in lymphoid organs, NK1.1+B220+CD11c+ appear to be the murine equivalent of human CD56bright NK cells.
doi:10.1084/jem.20070991
PMCID: PMC2118497  PMID: 17923504
11.  Organ-dependent in vivo priming of naive CD4+,but not CD8+,T cells by plasmacytoid dendritic cells 
The Journal of Experimental Medicine  2007;204(8):1923-1933.
Plasmacytoid dendritic cells (PDCs) play a pivotal role as cytokine-secreting accessory cells in the antimicrobial immune defense. In contrast, the capacity of PDCs to act as antigen-presenting cells in naive T cell priming remains unclear. By studying T cell responses in mice that lack conventional DCs (cDCs), and by the use of a PDC-specific antigen-targeting strategy, we show that PDCs can initiate productive naive CD4+ T cell responses in lymph nodes, but not in the spleen. PDC-triggered CD4+ T cell responses differed from cDC-driven responses in that they were not associated with concomitant CD8+ T cell priming. Our results establish PDCs as a bona fide DC subset that initiates unique CD4+ Th cell–dominated primary immune responses.
doi:10.1084/jem.20062373
PMCID: PMC2118686  PMID: 17646404
12.  Plasmacytoid Dendritic Cells Capture and Cross-Present Viral Antigens from Influenza-Virus Exposed Cells 
PLoS ONE  2009;4(9):e7111.
Among the different subsets of dendritic cells (DC), plasmacytoid dendritic cells (PDC) play a unique role in secreting large amounts of type I interferons upon viral stimulation, but their efficiency as antigen-presenting cells has not been completely characterized. We show here, by flow cytometry, with human primary blood PDC and with a PDC cell line, that PDC display poor endocytic capacity for soluble or cellular antigens when compared to monocyte-derived myeloid DC. However, immature PDC efficiently take up cellular material from live influenza-exposed cells, subsequently mature and cross-present viral antigens very efficiently to specific CD8+ T cells. Therefore, during viral infection PDC not only secrete immunomodulatory cytokines, but also recognize infected cells and function as antigen cross-presenting cells to trigger the anti-viral immune response.
doi:10.1371/journal.pone.0007111
PMCID: PMC2741572  PMID: 19771163
13.  Virus-induced Interferon α Production by a Dendritic Cell Subset in the Absence of Feedback Signaling In Vivo 
An effective type I interferon (IFN-α/β) response is critical for the control of many viral infections. Here we show that in vesicular stomatitis virus (VSV)-infected mouse embryonic fibroblasts (MEFs) the production of IFN-α is dependent on type I IFN receptor (IFNAR) triggering, whereas in infected mice early IFN-α production is IFNAR independent. In VSV-infected mice type I IFN is produced by few cells located in the marginal zone of the spleen. Unlike other dendritic cell (DC) subsets, FACS®-sorted CD11cintCD11b−GR-1+ DCs show high IFN-α expression, irrespective of whether they were isolated from VSV-infected IFNAR-competent or -deficient mice. Thus, VSV preferentially activates a specialized DC subset presumably located in the marginal zone to produce high-level IFN-α largely independent of IFNAR feedback signaling.
doi:10.1084/jem.20011666
PMCID: PMC2193622  PMID: 11854363
IFN type I; virus infection; dendritic cell subsets; IFN regulatory factor 7; type I IFN receptor
14.  Virus-specific antigen presentation by different subsets of cells from lung and mediastinal lymph node tissues of influenza virus-infected mice. 
Journal of Virology  1995;69(10):6359-6366.
Immune responses at mucosal sites are thought to be initiated in the draining lymph nodes, where dendritic cells present viral antigens and induce naive T cells to proliferate and to become effectors. Formal proof that antigen-presenting cells (APC) do indeed localize to the regional lymph nodes has been lacking for viral infections of the respiratory tract. Influenza virus was detected in the draining mediastinal lymph nodes (MLN) early after intranasal inoculation, with peak virus titers in this tissue measured at 2 days postinfection. Virus-specific cytotoxic T-lymphocyte responses were first detected in the MLN 1 day later. Macrophages, dendritic cells, and B lymphocytes were isolated from influenza virus-infected mice and assayed for the capacity to stimulate a major histocompatibility complex class I-restricted virus-specific T-cell hybridoma. All APC populations from lungs and MLN contained virus and thus had the potential to present antigen to CD8+ T cells. The APC recovered from the lungs of influenza virus-infected mice and dendritic cells from the MLN were able to stimulate virus-specific responses. The lack of a virus-specific T-cell response to B cells corresponds to the small number of virus-positive B lymphocytes in the MLN. These results indicate that dendritic cells and macrophages are antigen positive in mice acutely infected with an influenza A virus and that dendritic cells are probably responsible for initiating the cytotoxic T-lymphocyte response to influenza virus in the draining lymph nodes.
PMCID: PMC189535  PMID: 7666537
15.  Plasmacytoid Dendritic Cells in Tolerance 
Dendritic cells (DC) are professional antigen-presenting cells (APCs) that modulate the outcome of the immune response toward immunity or tolerance. There are a large variety of DC subsets according to surface phenotype, function, and tissue distribution. Murine plasmacytoid DC (pDC) represent a distinctive DC population and are characterized by the expression of CD11c, B220, Gr-1, CD45RA, Ly49Q, BST2, and siglec-H on the cell surface. PDC act as immunogenic cell sentinels by secreting large amounts of type I interferon (IFN) in the lymph nodes in response to viral stimulation. PDC also act as tolerogenic cells when expressing the inducible tolerogenic enzyme indoleamine 2,3-dioxygenase (IDO), the inducible costimulator ligand (ICOS-L), and/or the programmed death 1 ligand (PD-L1), which mediate regulatory T-cell (Treg) development and suppression of self- and alloreactive cells. The PDC ability to induce Treg development is associated with capture and presentation of antigenic peptides associated with major histocompatibility complex (MHC) class I and II. Here, we provide the tools to study PDC development from bone marrow cultures, their antigen presentation properties, and their interactions with Treg under a tolerogenic setting of sterile inflammation.
doi:10.1007/978-1-60761-869-0_9
PMCID: PMC3721973  PMID: 20941607
Plasmacytoid dendritic cells; Antigen presentation; Regulatory T cells
16.  Dendritic Cells Are Responsible for the Capacity of CpG Oligodeoxynucleotides to Act as an Adjuvant for Protective Vaccine Immunity Against Leishmania major in Mice 
Vaccination with leishmanial Ag and CpG oligodeoxynucleotides (ODN) confers sustained cellular immunity and protection to infectious challenge up to 6 mo after immunization. To define the cellular mechanism by which CpG ODN mediate their adjuvant effects in vivo, the functional capacity of distinct dendritic cell (DC) subsets was assessed in the lymph nodes (LNs) of BALB/c mice, 36 h after immunization with the leishmanial antigen (LACK) and CpG ODN. After this immunization, there was a striking decrease in the frequency of the CD11c+B220+ plasmacytoid DCs with a proportionate increase in CD11c+CD8−B220− cells. CD11c+CD8+B220− cells were the most potent producers of interleukin (IL)-12 p70 and interferon (IFN)-γ, while plasmacytoid DCs were the only subset capable of secreting IFN-α. In terms of antigen presenting capacity, plasmacytoid DCs were far less efficient compared with the other DC subsets. To certify that DCs were responsible for effective vaccination, we isolated CD11c+ and CD11c− cells 36 h after immunization and used such cells to elicit protective immunity after adoptive transfer in naive, Leishmania major susceptible BALB/c mice. CD11c+ cells but not 10-fold higher numbers of CD11c− cells from such immunized mice mediated protection. Therefore, the combination of LACK antigen and CpG ODN adjuvant leads to the presence of CD11c+ DCs in the draining LN that are capable of vaccinating naive mice in the absence of further antigen or adjuvant.
doi:10.1084/jem.20030645
PMCID: PMC2194077  PMID: 12874261
plasmacytoid dendritic cell; Toll-like receptor; Leishmania major; vaccine; Th1 cells
17.  Maturation, Activation, and Protection of Dendritic Cells Induced by Double-stranded RNA  
The initiation of an immune response is critically dependent on the activation of dendritic cells (DCs). This process is triggered by surface receptors specific for inflammatory cytokines or for conserved patterns characteristic of infectious agents. Here we show that human DCs are activated by influenza virus infection and by double-stranded (ds)RNA. This activation results not only in increased antigen presentation and T cell stimulatory capacity, but also in resistance to the cytopathic effect of the virus, mediated by the production of type I interferon, and upregulation of MxA. Because dsRNA stimulates both maturation and resistance, DCs can serve as altruistic antigen-presenting cells capable of sustaining viral antigen production while acquiring the capacity to trigger naive T cells and drive polarized T helper cell type 1 responses.
PMCID: PMC2192946  PMID: 10049946
dendritic cell maturation and activation; influenza virus; double-stranded RNA; type I interferon; MxA
18.  Dendritic Cell Responses to Early Murine Cytomegalovirus Infection 
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.
doi:10.1084/jem.20021522
PMCID: PMC2193893  PMID: 12682109
plasmacytoid dendritic cell; interferon α/β; murine cytomegalovirus; antigen presentation; CD8 T lymphocyte
19.  Anti-viral activity induced by culturing lymphocytes with tumor-derived or virus-transformed cells. Enhancement of human natural killer cell activity by interferon and antagonistic inhibition of susceptibility of target cells to lysis 
The Journal of Experimental Medicine  1978;147(5):1314-1333.
Interferon, induced in lymphocytes either with viruses or cell lines, increases severalfold the natural cytotoxicity of human lymphocytes on target cell lines. Cell separation experiments support the hypothesis that interferon enhances the activity of natural killer cells rather than generating a new population of effector cells. In mixed culture of lymphocytes and cell lines in which endogenous interferon is produced, interferon mediates an enhancement of cytotoxicity that represents up to 70-90% of the observed cytotoxicity. The effect of interferon on target cells is antagonistic to the effect on the lymphocytes: the susceptibility to cell-mediated lysis of various cells upon pretreatment with interferon is decreased and in some cases almost completely suppressed. Interferon renders target cells resistant to natural killer cells acting by an intracellular mechanism which requires RNA and protein synthesis. While normal fibroblasts are protected, virus-infected cells and most tumor cells usually are not protected by interferon. Interferon by stimulating very efficient nonspecific cytotoxic cells and by protecting at the same time normal cells from lysis, might render the natural killer cell system an inducible selective defense mechanism against tumor and virus-infected cells.
PMCID: PMC2184280  PMID: 650156
20.  Polarization of Allogeneic T-Cell Responses by Influenza Virus-Infected Dendritic Cells 
Journal of Virology  2000;74(17):7738-7744.
The developing immune response in the lymph nodes of mice infected with influenza virus has both Th1- and Th2-type characteristics. Modulation of the interactions between antigen-presenting cells and T cells is one mechanism that may alter the quality of the immune response. We have previously shown that the ability of dendritic cells (DC) to stimulate the proliferation of alloreactive T cells is changed by influenza virus due to viral neuraminidase (NA) activity. Here we show that DC infected with influenza virus A/PR/8/34 (PR8) stimulate T cells to produce different types of cytokines in a dose-dependent manner. Optimal amounts of the Th1-type cytokines interleukin-2 (IL-2) and gamma interferon (IFN-γ) were produced from T cells stimulated by DC infected with low doses of PR8, while the Th2-type cytokines IL-4 and IL-10 were produced only in response to DC infected with high doses of PR8. IL-2 and IFN-γ levels corresponded with T-cell proliferation and were dependent on the activity of viral NA on the DC surface. In contrast, IL-4 secretion required the treatment of T cells with NA. Since viral particles were released only from DC that are infected with high doses of PR8, our results suggest that viral NA on newly formed virus particles desialylates T-cell surface molecules to facilitate a Th2-type response. These results suggest that the activity of NA may contribute to the mixed Th-type response observed during influenza virus infection.
PMCID: PMC112302  PMID: 10933679
21.  Senescence-accelerated Mice (SAMs) as a Model for Brain Aging and Immunosenescence 
Aging and Disease  2011;2(5):414-435.
The Senescence-Accelerated Mouse (SAM) represents a group of inbred mouse strains developed as a model for the study of human aging and age-related diseases. Senescence-prone (SAMP) strains exhibit an early onset of age-related decline in the peripheral immunity such as thymic involution, loss of CD4+ T cells, impaired helper T cell function, decreased antibody-forming capacity, dysfunction of antigen-presenting cells, decreased natural killer activity, increased auto-antibodies, and susceptibility to virus infection. Senescence-prone SAMP10 mice undergo age-related changes in the brain such as brain atrophy, shrinkage and loss of cortical neurons, retraction of cortical neuronal dendrites, loss of dendritic spines, loss of synapses, impaired learning and memory, depressive behavior, accumulation of neuronal DNA damage, neuronal ubiquitinated inclusions, reduced hippocampal cholinergic receptors, decreased neurotrophic factors, decreased hippocampal zinc and zinc transporters, increased sphyngomyelinase, and elevated oxidative-nitrative stress. Recent data indicating increased pro-inflammatory cytokines in the brain of SAMP10 mice are directing investigators toward an integration of immune and neural abnormalities to enhance understanding of the principles of brain aging. We highlight how mouse brain cells adopt cytokine-mediated responses and how SAMP10 mice are defective in these responses. SAMP10 model would be useful to study how age-related disturbances in peripheral immunity have an impact on dysregulation of brain tissue homeostasis, resulting in age-related neurodegeneration.
PMCID: PMC3295080  PMID: 22396891
Brain Aging; Senescence-accelerated Mice; Immunosenescence; Model; CD4; T cells
22.  Interferon-producing Cells Fail to Induce Proliferation of Naive T Cells but Can Promote Expansion and T Helper 1 Differentiation of Antigen-experienced Unpolarized T Cells 
Interferon-producing cells (IPCs) secrete high levels of type I interferon in response to certain viruses. The lack of lineage markers, the expression of major histocompatibility complex (MHC) class II and the capacity to stimulate allogeneic T cells have led these cells to be classified as a subset of dendritic cells (DCs), called plasmacytoid DCs (PDCs). However, the role of IPCs/PDCs in initiating primary immune responses remains elusive. Here we examined the antigen presenting capacity of murine IPCs in antigen specific systems. While CD8α+ and CD11b+ DCs induced logarithmic expansion of naive CD4 and CD8 T cells, without conferring T helper commitment at a first encounter, primary IPCs lacked the ability to stimulate naive T cells. However, when antigen-experienced, nonpolarized T cells expanded by classical DC subsets, were restimulated by IPCs, they proliferated and produced high amounts of IFN-γ. These data indicate that IPCs can effectively stimulate preactivated or memory-type T cells and exert an immune-regulatory role. They also suggest that expansion of naive T cells and acquisition of effector function during antigen-specific T cell responses may involve different antigen-presenting cell (APC) types. Independent and coordinated control of T cell proliferation and differentiation would provide the immune system with greater flexibility in regulating immune responses.
doi:10.1084/jem.20021091
PMCID: PMC2193898  PMID: 12668648
interferon-producing cells; dendritic cells; Th1 cells; unpolarized T cells
23.  Regulation of STAT signaling in mouse bone marrow derived dendritic cells by respiratory syncytial virus 
Virus research  2011;156(0):127-133.
Background/aims
Dendritic cells (DCs) act as a portal for virus invasion as well as potent antigen-presenting cells (APCs) involved in the antiviral host response. Interferons (IFNs) are produced in response to bacterial and viral infection and activate innate immune responses to efficiently counteract and remove pathogenic invaders. Respiratory syncytial virus (RSV) could inhibit IFN-mediated signaling pathway in epithelial cells; however, the effects of RSV on IFN signaling in the dendritic cells (DCs) are still unknown.
Methods
Mouse bone marrow derived DCs (BMDCs) were mock or infected with RSV at different multiplicity of infection (MOI) for 24 h, and then treated with different cytokines such as interferon-β (IFN-β), IFN-γ or interleukin-10 (IL-10). The mRNA expression of RSV nonstructural protein-1 (NS-1) and NS-2 was detected by RT-PCR. The expression of Janus family kinase-signal transducer and activator of transcription (JAK/STAT) signaling proteins was assessed by immunoblotting assays. The nuclear localization of specific signaling proteins was determined by immunofluorescence assay.
Results
Increasing amounts of NS-1 or NS-2 mRNA expression in BMDCs were observed with infected RSV at increasing MOI, suggesting BMDCs were permissive for viral gene expression. Further examination of the IFN-β signaling cascade showed RSV infection increased the total cellular levels of STAT1 and STAT2 in BMDCs, but impaired the IFN-β-dependent phosphorylation and nuclear localization of STAT1 and STAT2. The inhibitory effects of RSV on STAT1 and STAT2 phosphorylation and translocation were abolished by UV inactivation. In contrast, RSV did not inhibit the IFN-γ-stimulated STAT1 phosphorylation and nuclear localization. IL-10-stimulated STAT3 phosphorylation was also unaffected by RSV.
Conclusions
As well as RSV inhibiting STAT protein levels through degradation mechanisms in epithelial cells, these findings demonstrate that RSV also can specifically inhibit the type I interferon response in BMDCs through regulation of STAT1 and STAT2 phosphorylation and nuclear translocation.
doi:10.1016/j.virusres.2011.01.007
PMCID: PMC3726278  PMID: 21255624
Bone marrow derived dendritic cells; Respiratory syncytial virus; Type I interferon; STAT; Signal pathway
24.  Multiple Dendritic Cell Populations Activate CD4+ T Cells after Viral Stimulation 
PLoS ONE  2008;3(2):e1691.
Dendritic cells (DC) are a heterogeneous cell population that bridge the innate and adaptive immune systems. CD8α DC play a prominent, and sometimes exclusive, role in driving amplification of CD8+ T cells during a viral infection. Whether this reliance on a single subset of DC also applies for CD4+ T cell activation is unknown. We used a direct ex vivo antigen presentation assay to probe the capacity of flow cytometrically purified DC populations to drive amplification of CD4+ and CD8+ T cells following infection with influenza virus by different routes. This study examined the contributions of non-CD8α DC populations in the amplification of CD8+ and CD4+ T cells in cutaneous and systemic influenza viral infections. We confirmed that in vivo, effective immune responses for CD8+ T cells are dominated by presentation of antigen by CD8α DC but can involve non-CD8α DC. In contrast, CD4+ T cell responses relied more heavily on the contributions of dermal DC migrating from peripheral lymphoid tissues following cutaneous infection, and CD4 DC in the spleen after systemic infection. CD4+ T cell priming by DC subsets that is dependent upon the route of administration raises the possibility that vaccination approaches could be tailored to prime helper T cell immunity.
doi:10.1371/journal.pone.0001691
PMCID: PMC2253497  PMID: 18301768
25.  Connecting the Dots: Artificial Antigen Presenting Cell-Mediated Modulation of Natural Killer T Cells 
Natural killer T (NKT) cells constitute an important subset of T cells that can both directly and indirectly mediate antitumor immunity. However, we and others have reported that cancer patients have a reduction in both NKT cell number and function. NKT cells can be stimulated and expanded with α-GalCer and cytokines and these expanded NKT cells retain their phenotype, remain responsive to antigenic stimulation, and display cytotoxic function against tumor cell lines. These data strongly favor the use of ex vivo expanded NKT cells in adoptive immunotherapy. NKT cell based-immunotherapy has been limited by the use of autologous antigen-presenting cells, which can vary substantially in their quantity and quality. A standardized system that relies on artificial antigen-presenting cells (aAPCs) could produce the stimulating effects of dendritic cell (DC) without the pitfalls of allo- or xenogeneic cells. In this review, we discuss the progress that has been made using CD1d-based aAPC and how this acellular antigen presenting system can be used in the future to enhance our understanding of NKT cell biology and to develop NKT cell-specific adoptive immunotherapeutic strategies.
doi:10.1089/jir.2012.0045
PMCID: PMC3493043  PMID: 23050947

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