HIV-1-infected dendritic cells up-regulate cell surface markers but fail to produce IL-12 p70 in response to CD40 ligand stimulation. Blood

Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, F59 Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden.
Blood (Impact Factor: 10.45). 12/2004; 104(9):2810-7. DOI: 10.1182/blood-2003-07-2314
Source: PubMed


Dendritic cells (DCs) are antigen-presenting cells with the capacity to prime naive T cells for efficient cellular responses against pathogens such as HIV-1. DCs are also susceptible to HIV-1 infection, which may impair their ability to induce immunity. Here, we examined the ability of HIV-1-infected, in vitro-derived DCs to respond to CD40 ligand (CD40L) stimulation with the aim to study events during early HIV-1 infection. HIV-1(BaL)-infected p24(+) DCs were detected after only 3 days of exposure to highly concentrated virus. We show that HIV-1-infected DCs up-regulated costimulatory molecules, but were skewed in their production of effector cytokines in response to CD40L stimulation. CD40L stimulation induced significant secretion of tumor necrosis factor alpha (TNFalpha) and interleukin 12 (IL-12) p70 from both HIV-1-exposed and unexposed DCs. Intracellular stainings of HIV-1-exposed DCs revealed that TNFalpha could be detected in both the p24(-) and p24(+) DCs, but IL-12 p70 could be found only in the p24(-) DCs. Thus, although p24(+) DCs showed a mature phenotype similar to p24(-) DCs after CD40L stimulation, they appeared to have an impaired cytokine profile. These observations suggest that HIV-1 infection disables DC function, a phenomenon that may be relevant for optimal induction of HIV-1-specific immune responses.

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Available from: Jan Andersson, May 06, 2014
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    • "Dendritic cells are key determinants of normal NK cell maturation and development, and are an important source of IL-12, known to be required for NK cell activation [40], [47]. Dendritic cells have been shown to produce sub-normal quantities of IL-12 and other cytokines in normal newborns [45] and in HIV-infected individuals [46], [48]. Exposure to IL-2, IL-12 and IL-15 improves cytotoxic effector responses in CD56neg NK cells from newborn infants [11], [16]. "
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    ABSTRACT: Neonatal Natural Killer (NK) cells show functional impairment and expansion of a CD56 negative population of uncertain significance. NK cells were isolated from cord blood and from adult donors. NK subpopulations were identified as positive or negative for the expression of CD56 and characterized for expression of granzyme B and surface markers by multi-parameter flow cytometry. Cell function was assessed by viral suppression and cytokine production using autologous lymphocytes infected with HIV. Activating (NKp30, NKp46) and inhibitory (Siglec-7) markers in healthy infants and adults were compared with viremic HIV-infected adults. Cord blood contained increased frequencies of CD56 negative (CD56neg) NK cells with reduced expression of granzyme B and reduced production of IFNγ and the CC-class chemokines RANTES, MIP1α and MIP1β upon stimulation. Both CD56pos and CD56neg NK subpopulations showed impaired viral suppression in cord blood, with impairment most marked in the CD56neg subset. CD56neg NK cells from cord blood and HIV-infected adults shared decreased inhibitory and activating receptor expression when compared with CD56pos cells. CD56neg NK cells are increased in number in normal infants and these effectors show reduced anti-viral activity. Like the expanded CD56neg population described in HIV-infected adults, these NK cells demonstrate functional impairments which may reflect inadequate development or activation.
    PLoS ONE 06/2013; 8(6):e67700. DOI:10.1371/journal.pone.0067700 · 3.23 Impact Factor
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    • "Viral infection Impaired maturation/function (Virus-dependent) Downregulation of CD1a, CD1b, DC-SIGN, CD80, CD83, CD86 IFNα, IL-10, IL-1β (missing IL-12, IL-6, TNFα secretion) Kruse et al., 2000; Sarobe et al., 2003; Smed-Sorensen et al., 2004; Martinson et al., 2007; Tilton et al., 2008; Harman et al., 2011; Chentoufi et al., 2012; Dental et al., 2012; Tu et al., 2012 "
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    ABSTRACT: The immune system exists in a delicate equilibrium between inflammatory responses and tolerance. This unique feature allows the immune system to recognize and respond to potential threats in a controlled but normally limited fashion thereby preventing a destructive overreaction against healthy tissues. While the adaptive immune system was the major research focus concerning activation versus tolerance in the immune system more recent findings suggest that cells of the innate immune system are important players in the decision between effective immunity and induction of tolerance or immune inhibition. Among immune cells of the innate immune system dendritic cells (DCs) have a special function linking innate immune functions with the induction of adaptive immunity. DCs are the primary professional antigen presenting cells (APCs) initiating adaptive immune responses. They belong to the hematopoietic system and arise from CD34+ stem cells in the bone marrow. Particularly in the murine system two major subgroups of DCs, namely myeloid (mDCs) and plasmacytoid DCs (pDCs) can be distinguished. DCs are important mediators of innate and adaptive immunity mostly due to their remarkable capacity to present processed antigens via major histocompatibility complexes (MHC) to T cells and B cells in secondary lymphoid organs. A large body of literature has been accumulated during the last two decades describing which role DCs play during activation of T cell responses but also during the establishment and maintenance of central tolerance (Steinman et al., 2003). While the concept of peripheral tolerance has been clearly established during the last years, the role of different sets of DCs and their particular molecular mechanisms of immune deviation has not yet fully been appreciated. In this review we summarize accumulating evidence about the role of regulatory dendritic cells in situations where the balance between tolerance and immunogenicity has been altered leading to pathologic
    Frontiers in Immunology 09/2012; 3:274. DOI:10.3389/fimmu.2012.00274
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    • "Due to their location at mucosal surfaces and their expression of HIV receptors, DCs are important targets of HIV infection. HIV-infected myeloid DCs exhibit defective maturation even upon strong microbial stimulation [45], [46], a result confirmed by our study, although opposite results were obtained if HIV-1 Bal infected DCs were stimulated by CD40L [47]. How these defects affect the ability of circulating DCs to induce Tregs is poorly understood, and clarifying this issue was the goal of our study. "
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    ABSTRACT: Myeloid dendritic cells (mDCs) are the antigen-presenting cells best capable of promoting peripheral induction of regulatory T cells (Tregs), and are among the first targets of HIV. It is thus important to understand whether HIV alters their capacity to promote Treg conversion. Monocyte-derived DCs (moDCs) from uninfected donors induced a Treg phenotype (CD25(+)FOXP3(+)) in autologous conventional T cells. These converted FOXP3(+) cells suppressed the proliferation of responder T cells similarly to circulating Tregs. In contrast, the capacity of moDCs to induce CD25 or FOXP3 was severely impaired by their in vitro infection with CCR5-utilizing virus. MoDC exposure to inactivated HIV was sufficient to impair FOXP3 induction. This DC defect was not dependent on IL-10, TGF-β or other soluble factors, but was due to preferential killing of Tregs by HIV-exposed/infected moDCs, through a caspase-dependent pathway. Importantly, similar results were obtained with circulating primary myeloid DCs. Upon infection in vitro, these mDCs also killed Treg through mechanisms at least partially caspase-dependent, leading to a significantly lower proportion of induced Tregs. Taken together, our data suggest that Treg induction may be defective when DCs are exposed to high levels of virus, such as during the acute phase of infection or in AIDS patients.
    PLoS ONE 08/2012; 7(8):e42802. DOI:10.1371/journal.pone.0042802 · 3.23 Impact Factor
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