Induction of tolerogenic vs immunogenic dendritic cells (DCs) in the presence of GM-CSF is regulated by the strength of signaling from monophosphoryl lipid A (MPLA) in association with glutathione and fetal hemoglobin gamma-chain

Khatri, Ismat; Alexander, Christian; Brandenburg, Klaus; Fournier, K.; Mach, Jean‐Pierre; Rietschel, Ernst; Ulmer, Artur J.; Terzıoğlu, Ender; Waelli, Thierry; Gorczynski, Reg

doi:10.1016/j.imlet.2009.04.002

Cited by 6 publications

(4 citation statements)

References 39 publications

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“…This is in accordance with the conclusion of several authors that the cytokine profile, rather than maturation status, is much more indicative of the tolerogenic properties of DCs (40)(41)(42). These data are also consistent with the ability of IL-10 and GM-CSF to promote the differentiation of Treg-inducing tDCs (43)(44)(45)(46)(47)(48)(49). The increased production of IL-10 by CD4 + and CD14 + cells is of particular interest, as IL-10 skews GM-CSF-/IL-4induced MoDC toward a tolerogenic phenotype (50).…”

Section: Discussionsupporting

confidence: 93%

Ex Vivo Expansion of Human Tregs by Rabbit ATG Is Dependent on Intact STAT3-Signaling in CD4+ T Cells and Requires the Presence of Monocytes

Boenisch

Lopez

Elyaman

et al. 2012

American Journal of Transplantation

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The addition of low, nondepleting doses of rabbit antithymocyte globulin (ATG) to human peripheral blood mononuclear cells has been shown to expand functional CD4+CD25+FoxP3+ regulatory T cells (Tregs) in vitro. This report is the first to elucidate the exact cellular mechanisms of ATG-mediated Treg expansion. CD4+ T cells require monocytes, but not other antigen presenting cell subsets, to be present in coculture to expand Tregs. However, T cells do not require direct cell–cell contact with monocytes, suggesting the importance of soluble factors. Moreover, ATG initially “reprograms” CD4+ T cells, but not monocytes, and induces STAT3 and STAT5 signaling in CD4+ cells. These reprogrammed CD4+ T cells subsequently secrete GM-CSF and IL-10 only in case of intact STAT3 signaling, which in turn promote the generation of tolerogenic CD14+CD11c+ dendritic cells characterized by enhanced IL-10 and decreased IL-12 production. Treg expansion following ATG treatment is accompanied by enhanced gene expression of both GM-CSF and Bcl-2, but not TGF-β, in peripheral blood mononuclear cells. These results demonstrate that ex vivo expansion of human Tregs by ATG is due to its ability to reprogram CD4+ T cells in a STAT3-dependent but TGF-β-independent manner, leading to the generation of monocyte-derived dendritic cells with a tolerogenic cytokine profile.

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Section: Discussionsupporting

confidence: 93%

Ex Vivo Expansion of Human Tregs by Rabbit ATG Is Dependent on Intact STAT3-Signaling in CD4+ T Cells and Requires the Presence of Monocytes

Boenisch

Lopez

Elyaman

et al. 2012

American Journal of Transplantation

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“…A recent example of lipid A analog is MPLA known to activate immune cells with similar properties of the LPS but less toxic and non immunogenic [34], [35]. Our results show that CβG-induced DC maturation is dependent on TLR4 as well as Myd88 and TRIF adaptor molecules.…”

Section: Discussionmentioning

confidence: 53%

Brucella β 1,2 Cyclic Glucan Is an Activator of Human and Mouse Dendritic Cells

Martirosyan

Pérez-Gutiérrez

Banchereau³

et al. 2012

PLoS Pathog

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Bacterial cyclic glucans are glucose polymers that concentrate within the periplasm of alpha-proteobacteria. These molecules are necessary to maintain the homeostasis of the cell envelope by contributing to the osmolarity of Gram negative bacteria. Here, we demonstrate that Brucella β 1,2 cyclic glucans are potent activators of human and mouse dendritic cells. Dendritic cells activation by Brucella β 1,2 cyclic glucans requires TLR4, MyD88 and TRIF, but not CD14. The Brucella cyclic glucans showed neither toxicity nor immunogenicity compared to LPS and triggered antigen-specific CD8+ T cell responses in vivo. These cyclic glucans also enhanced antigen-specific CD4+ and CD8+ T cell responses including cross-presentation by different human DC subsets. Brucella β 1,2 cyclic glucans increased the memory CD4+ T cell responses of blood mononuclear cells exposed to recombinant fusion proteins composed of anti-CD40 antibody and antigens from both hepatitis C virus and Mycobacterium tuberculosis. Thus cyclic glucans represent a new class of adjuvants, which might contribute to the development of effective antimicrobial therapies.

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“…It has been reported recently that only strong TLR4 signaling prompted DCs to induce regulatory T cells in vitro. 102 In conclusion, the picture emerges that tolerogenic DC properties through TLR signaling are critically influenced by constant exposure to TLR ligands, the coactivation of certain TLRs, and the strength of TLR activation.…”

Section: Tlr Activation On Dcs Enforces Tolerance: the Other Side Of mentioning

confidence: 99%

Dendritic cells: Bridging innate and adaptive immunity in atopic dermatitis

Novak¹,

Koch²,

Allam³

et al. 2010

Journal of Allergy and Clinical Immunology

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Induction of tolerogenic vs immunogenic dendritic cells (DCs) in the presence of GM-CSF is regulated by the strength of signaling from monophosphoryl lipid A (MPLA) in association with glutathione and fetal hemoglobin gamma-chain

Cited by 6 publications

References 39 publications

Ex Vivo Expansion of Human Tregs by Rabbit ATG Is Dependent on Intact STAT3-Signaling in CD4+ T Cells and Requires the Presence of Monocytes

Ex Vivo Expansion of Human Tregs by Rabbit ATG Is Dependent on Intact STAT3-Signaling in CD4+ T Cells and Requires the Presence of Monocytes

Brucella β 1,2 Cyclic Glucan Is an Activator of Human and Mouse Dendritic Cells

Dendritic cells: Bridging innate and adaptive immunity in atopic dermatitis

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