STAT3-silenced human dendritic cells have an enhanced ability to prime IFNγ production by both αβ and γδ T lymphocytes

Sanseverino, Isabella; Purificato, Cristina; Varano, Barbara; Conti, Lucia; Gessani, Sandra; Gauzzi, Maria Cristina

doi:10.1016/j.imbio.2014.02.012

Cited by 13 publications

(11 citation statements)

References 34 publications

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“…In keeping with this hypothesis, it has been reported recently that exposure of PBMCs to gp120 leads to MDSC expansion via gp120-induced IL-6 and STAT3 activation (51). Furthermore, some studies, including ours, have shown that blocking STAT3 activity enhances DC allostimulatory capacity (20,38) and renders these cells more resistant to immunosuppressive environments, such as that generated at tumor sites (20).…”

Section: Discussionsupporting

confidence: 69%

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HIV-1 gp120 Activates the STAT3/Interleukin-6 Axis in Primary Human Monocyte-Derived Dendritic Cells

Cornò

Donninelli

Varano

et al. 2014

J Virol

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Dendritic cells (DCs IMPORTANCEThis study provides new evidence for the molecular mechanisms and signaling pathways triggered by HIV-1 gp120 in human DCs in the absence of productive infection, emphasizing a role of aberrant signaling in early virus-host interaction, contributing to viral pathogenesis. We identified STAT3 as a key component in the gp120-mediated signaling cascade involving MAPK and NF-B components and ultimately leading to IL-6 secretion. STAT3 now is recognized as a key regulator of DC functions. Thus, the identification of this transcription factor as a signaling molecule mediating some of gp120's biological effects unveils a new mechanism by which HIV-1 may deregulate DC functions and contribute to AIDS pathogenesis.

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Section: Discussionsupporting

confidence: 69%

“…We recently reported that efficient STAT3 silencing in primary DCs is limited, and that transfection per se induces cellular activation (38). Therefore, validation of STAT3 involvement in gp120-induced IL-6 production by STAT3 knockdown was not successful (data not shown).…”

Section: Resultsmentioning

confidence: 94%

HIV-1 gp120 Activates the STAT3/Interleukin-6 Axis in Primary Human Monocyte-Derived Dendritic Cells

Cornò

Donninelli

Varano

et al. 2014

J Virol

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“…The activating effect of STAT3 is at least in part mediated by increased IL-12 production and STAT3 silencing in mo-DCs enhances IFN-g production of gd T cells. 73 IFN-a/b, produced by CD11c C DCs, contribute to the activation of gd T cells by poly(I:C). 61 Type I IFNs play also an important role in TLR-matured DCgd T cell activation, shown by a §80% reduction of the induced IFN-g secretion by blocking IFNAR2.…”

Section: Mechanisms Behind Dc-mediated Gd T Cell Activationmentioning

confidence: 99%

Empowering gamma delta T cells with antitumor immunity by dendritic cell-based immunotherapy

Anguille

et al. 2015

OncoImmunology

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These authors equally contributed to the work.Keywords: gd T cell, cancer, DC-mediated gd T cell activation, dendritic cell, immunotherapy Abbreviations: gd, gamma delta; BCG, Bacillus Calmette-Guerin; BrHPP, bromohydrin pyrophosphate; CTL, cytotoxic T lymphocyte; DC, dendritic cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; HIV, human immunodeficiency virus; HMBPP, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate; iDC, immature DC; IFN, interferon; IL, interleukin; IPP, isopentyl pyrophosphate; mDC, myeloid dendritic cell; MHC, major histocompatibility complex; mo-DC, monocyte-derived dendritic cell; pDC, plasmacytoid dendritic cell; PD, programmed cell death protein; TCR, T-cell receptor; Th, T-helper cell; TLR, toll-like receptor; TNF, tumor necrosis factor; Treg, regulatory T cellGamma delta (gd) T cells are the all-rounders of our immune-system with their major histocompatibility complexunrestricted cytotoxicity, capacity to secrete immunostimulatory cytokines and ability to promote the generation of tumor antigen-specific CD8 C and CD4 C T cell responses. Dendritic cell (DC)-based vaccine therapy has the prospective to harness these unique features of the gd T cells in the fight against cancer. In this review, we will discuss our current knowledge on DC-mediated gd T cell activation and related opportunities for tumor immunologists.

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“…In this regard, it has been reported that IL-10 inhibits ␥␦ T cell proliferation and IFN-␥ production in the presence of monocytes (45). Furthermore, we have recently reported that manipulating the IL-10/IL-12 balance by either blocking endogenous IL-12 or exogenously adding IL-10 significantly decreases IFN-␥ production in antigen-stimulated DC/␥␦ T cell cocultures (46), thus suggesting a crucial role for antigenpresenting cell (APC)-specific cytokines in shaping the ␥␦ T lymphocyte response. In keeping with our findings, Wesch and colleagues reported that the failure of V␦2 cells from HIV ϩ individuals to proliferate in response to mycobacterial antigens is not an intrinsic defect of this cell subset and that the responsiveness can be restored following reconstitution with APCs from allogeneic donors (9).…”

Section: Discussionmentioning

confidence: 99%

HIV-1-Induced Impairment of Dendritic Cell Cross Talk with γδ T Lymphocytes

Cardone

Ikeda

Varano

et al. 2015

J Virol

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The interplay between dendritic cells (DC) and ␥␦ ⌻ lymphocytes represents a network of paracrine and cell contact interactions important for an integrated immune response to pathogens. HIV-1 infection dramatically affects the number and functions of both cell populations, and DC/␥␦ ⌻ cell cross talk may represent a target of virus-induced immune escape. We investigated whether HIV-exposed DC could deliver aberrant signals to interacting ␥␦ ⌻ cells. Here we report that the interaction of human ␥␦ T lymphocytes with HIV-1-exposed autologous monocyte-derived DC, but not direct exposure to the virus, impairs lymphocyte expansion and gamma interferon (IFN-␥) production in response to phosphoantigens. This effect is independent of virus strain and occurred in 55% of the donors analyzed. The donor-dependent variation observed relies on the responsiveness of DC to HIV-1 and is strictly related to the capacity of the virus to suppress the maturation-induced expression of interleukin 12 (IL-12). In fact, ␥␦ T cell response to phosphoantigens is almost completely recovered when this cytokine is exogenously added to the DC/lymphocyte cocultures. Interestingly, we show that ␥␦ T lymphocytes are recruited by HIV-1-exposed DC through a CCR5-mediated mechanism and exert a CCL4-mediated control on virus dissemination within DC and susceptible CD4 ؉ T lymphocytes. These results demonstrate an association between HIV-induced DC dysfunction and alterations of ␥␦ T cell responses. The aberrant cross talk between these two cell populations may contribute to the pathogenesis of HIV infection by further reducing the strength of antiviral immune response. IMPORTANCEThis study provides new evidence on the mechanisms exploited by HIV-1 to evade the host immune response. We report that HIV-1 impairs the cross talk between DC and ␥␦ T lymphocytes, by reducing the capacity of DC to promote functional ␥␦ T cell activation. Interestingly, the virus does not per se interfere with ␥␦ T cell activation, thus highlighting the key role of early DC-HIV-1 interaction in this phenomenon. Furthermore, the results obtained unravel the novel role of ␥␦ T cells in controlling HIV-1 dissemination within the DC population as well as virus transfer to susceptible CD4 ؉ T lymphocytes. The interactions of DC with innate lymphocytes represent a major control mechanism for an integrated immune response to infection. Understanding how HIV-1 harnesses these pathways may provide important insights on the pathogenesis of disease and offer new opportunities for therapeutic interventions.

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STAT3-silenced human dendritic cells have an enhanced ability to prime IFNγ production by both αβ and γδ T lymphocytes

Cited by 13 publications

References 34 publications

HIV-1 gp120 Activates the STAT3/Interleukin-6 Axis in Primary Human Monocyte-Derived Dendritic Cells

HIV-1 gp120 Activates the STAT3/Interleukin-6 Axis in Primary Human Monocyte-Derived Dendritic Cells

Empowering gamma delta T cells with antitumor immunity by dendritic cell-based immunotherapy

HIV-1-Induced Impairment of Dendritic Cell Cross Talk with γδ T Lymphocytes

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