A critical role for lipophosphoglycan in proinflammatory responses of dendritic cells to <i>Leishmania mexicana</i>

Aebischer, Toni; Bennett, Clare L.; Pelizzola, Mattia; Vizzardelli, Caterina; Pavelka, Norman; Urbano, Matteo; Capozzoli, Monica; Luchini, Alessandra; Ilg, Thomas; Granucci, Francesca; Blackburn, C. Clare; Ricciardi‐Castagnoli, Paola

doi:10.1002/eji.200425674

Cited by 39 publications

(35 citation statements)

References 54 publications

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“…1), suggesting that promastigotes of L. major do not contain component leading to complete DC maturation like TLR ligands. This is in agreement with a report showing that, with regard to DC activation, infection with L. major is a silent process (34). Thus, the absence of IL-12 secretion by TNF-DCs pulsed with L. major lysate might support the development of a non-protective Th2 response ( Figs.…”

Section: Discussionsupporting

confidence: 93%

“…1) and CD1d expression (Fig. 4D), which is in agreement with another previous report (34). These controversial results might be explained by the different DCs (BM-derived mouse DCs vs monocyte-derived human DCs), different Leishmania species (L. major causing cutaneous leishmaniasis vs L. infantum causing visceral leishmaniasis), and different types of Ag loading (pulsing with Leishmania lysate vs infection with live parasites) used in these studies.…”

Section: Discussionsupporting

confidence: 90%

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Dendritic Cell Differentiation State and Their Interaction with NKT Cells Determine Th1/Th2 Differentiation in the Murine Model ofLeishmania majorInfection

Wiethe¹,

Debus

Mohrs

et al. 2008

The Journal of Immunology

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Recent reports demonstrated that dendritic cells (DC) sense inflammatory and microbial signals differently, redefining their classical subdivision into an immature endocytic and a mature Ag-presenting differentiation stage. Although both signals induce DC maturation by up-regulating MHC class II and costimulatory molecules, only TLR signals such as LPS are able to trigger proinflammatory cytokine secretion by DCs, including Th1-polarizing IL-12. Here, we explored the murine Leishmania major infection model to examine the CD4+ T cell response induced by differentially matured DCs. When partially matured TNF-DCs were injected into BALB/c mice before infection, the mice failed to control L. major infection and developed a Th2 response which was dependent on IL-4Rα signaling. In contrast, injections of fully matured LPS+CD40-DCs induced a Th1 response controlling the infection. Pulsing DCs with a lysate of L. major did not affect DC maturation with TNF-α or LPS+anti-CD40. When the expression of different Notch ligands on DCs was analyzed, we found increased expression of Th2-promoting Jagged2 in TNF-DCs, whereas LPS+CD40-DCs up-regulated the Th1-inducing Delta4 and Jagged1 molecules. The Th2 polarization induced by TNF-DCs required interaction with CD1d-restricted NKT cells. However, NKT cell activation by L. major lysate-pulsed DCs was not affected by blockade of the endogenous glycolipid, suggesting exchange with exogenous parasite-derived CD1 glycolipid Ag. In sum, the differentiation stage of DCs as well as their interaction with NKT cells determines Th1/Th2 differentiation. These results have generic implications for the understanding of DC-driven Th cell responses and the development of improved DC vaccines against leishmaniasis.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 90%

Dendritic Cell Differentiation State and Their Interaction with NKT Cells Determine Th1/Th2 Differentiation in the Murine Model ofLeishmania majorInfection

Wiethe¹,

Debus

Mohrs

et al. 2008

The Journal of Immunology

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“…Studies in mice that exhibit LC deficiencies have changed this paradigm. Recent studies indicate that LC do not function as essential antigen-presenting cells in contact hypersensitivity reactions (10)(11)(12) or antiviral responses (13,14). Based on studies of contact hypersensitity (11,15) and cutaneous leishmaniasis (16), an immune-attenuating role for LC has been suggested.…”

mentioning

confidence: 99%

Cancer-associated epithelial cell adhesion molecule (EpCAM; CD326) enables epidermal Langerhans cell motility and migration in vivo

Gaiser

Lämmermann

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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After activation, Langerhans cells (LC), a distinct subpopulation of epidermis-resident dendritic cells, migrate from skin to lymph nodes where they regulate the magnitude and quality of immune responses initiated by epicutaneously applied antigens. Modulation of LC–keratinocyte adhesion is likely to be central to regulation of LC migration. LC express high levels of epithelial cell adhesion molecule (EpCAM; CD326), a cell-surface protein that is characteristic of some epithelia and many carcinomas and that has been implicated in intercellular adhesion and metastasis. To gain insight into EpCAM function in a physiologic context in vivo, we generated conditional knockout mice with EpCAM-deficient LC and characterized them. Epidermis from these mice contained increased numbers of LC with normal levels of MHC and costimulatory molecules and T-cell–stimulatory activity in vitro. Migration of EpCAM-deficient LC from skin explants was inhibited, but chemotaxis of dissociated LC was not. Correspondingly, the ability of contact allergen-stimulated, EpCAM-deficient LC to exit epidermis in vivo was delayed, and strikingly fewer hapten-bearing LC subsequently accumulated in lymph nodes. Attenuated migration of EpCAM-deficient LC resulted in enhanced contact hypersensitivity responses as previously described in LC-deficient mice. Intravital microscopy revealed reduced translocation and dendrite motility in EpCAM-deficient LC in vivo in contact allergen-treated mice. These results conclusively link EpCAM expression to LC motility/migration and LC migration to immune regulation. EpCAM appears to promote LC migration from epidermis by decreasing LC–keratinocyte adhesion and may modulate intercellular adhesion and cell movement within in epithelia during development and carcinogenesis in an analogous fashion.

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“…In this experiment we used full maturation, TLR-dependent and -independent microbial stimuli and full-maturation, nonmicrobial stimuli. The TLR-dependent microbial stimuli used were: LPS (TLR4), CpG (TLR9), Pam3Cys (TLR2) (26), BCG, and L. mexicana promastigote (27,28). The TLR-independent microbial stimuli were CT and PT.…”

Section: Only Dcs Activated With Tlr-dependent Microbial Stimuli Are mentioning

confidence: 99%

TLR-Dependent Activation Stimuli Associated with Th1 Responses Confer NK Cell Stimulatory Capacity to Mouse Dendritic Cells

Zanoni

Foti

Ricciardi‐Castagnoli

et al. 2005

The Journal of Immunology

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Dendritic cells (DCs) have an important role in the activation of NK cells that exert direct antitumor and antimicrobial effects and can influence the development of adaptive T cell responses. DCs acquire NK cell stimulatory capacity after exposure to various stimuli. In this study we investigated the nature of the stimuli that confer to DCs the NK cell-activating capacity. After exposure of DCs to TLR-dependent and -independent microbial stimuli and to nonmicrobial stimuli, we evaluated the ability of activated DCs to elicit IFN-γ production from NK cells in vitro and to promote NK cell activation in vivo. We show in this study that only TLR-dependent microbial stimuli typically associated with Th1 responses confer to DCs the ability to activate NK cells, whereas stimuli associated with Th2 responses do not have this property.

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A critical role for lipophosphoglycan in proinflammatory responses of dendritic cells to Leishmania mexicana

Cited by 39 publications

References 54 publications

Dendritic Cell Differentiation State and Their Interaction with NKT Cells Determine Th1/Th2 Differentiation in the Murine Model ofLeishmania majorInfection

Dendritic Cell Differentiation State and Their Interaction with NKT Cells Determine Th1/Th2 Differentiation in the Murine Model ofLeishmania majorInfection

Cancer-associated epithelial cell adhesion molecule (EpCAM; CD326) enables epidermal Langerhans cell motility and migration in vivo

TLR-Dependent Activation Stimuli Associated with Th1 Responses Confer NK Cell Stimulatory Capacity to Mouse Dendritic Cells

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