Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells

Langenkamp, Anja; Messi, Mara; Lanzavecchia, Antonio; Sallusto, Federica

doi:10.1038/79758

Cited by 1,021 publications

(942 citation statements)

References 49 publications

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“…It has been proposed that blocking or washing out IL-12p70 production is sufficient to drive the differentiation of Th2-cell responses by the so-called default or exhaustion pathway [64,65]. The elimination of IL-12p70 from the context of antigen presentation by mature DCs would result in a similar phenotype of inflammatory semi-mature DCs as we have generated them here.…”

Section: Discussionmentioning

confidence: 73%

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

Pletinckx

Stijlemans²,

Pavlović

et al. 2011

Eur J Immunol

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DCs represent the major cell type leading to polarized T-helper (Th) cell responses in vivo. Here, we asked whether the instruction of murine Th2 responses by DCs matured with the proinflammatory cytokine TNF is qualitatively different from maturation by different types of TLR4/MyD88-dependent variant-specific surface glycoproteins (VSGs) of Trypanosoma brucei (T. brucei). The results obtained by analyzing DC surface markers, Notch ligand mRNA, cytokines, asthma, and experimental autoimmune encephalomyelitis (EAE) models as well as performing microarrays indicate that both types of stimuli induce similar inflammatory, semi-mature DC profiles. DCs matured by TNF or VSG treatment expressed a common inflammatory signature of 24 genes correlating with their Th2-polarization capacity. However, the same 24 genes and 4498 additional genes were expressed by DCs treated with LPS that went on to induce Th1 cells. These findings support the concept of a default pathway for Th2-cell induction in DCs matured under suboptimal or inflammatory conditions, independent of the surface receptors and signaling pathways involved. Our data also indicate that quantitative differences in DC maturation might direct Th2-vs Th1-cell responses, since suboptimally matured inflammatory DCs induce default Th2-cell maturation, whereas fully mature DCs induce Th1-cell maturation.Key words: DCs . microarray . Th2 cells . TNF . Trypanosoma Supporting Information available online IntroductionDCs play a fundamental role in the induction of adaptive immune responses as well as in the maintenance of peripheral tolerance [1][2][3]. Through the expression of pattern-recognition receptors (PPRs) such as Toll-like receptors (TLRs), DCs are able to sense a wide array of pathogens and mount an appropriate T-helper (Th) cell response [4]. Naïve CD4 1 T-cell precursors can differentiate into a variety of Th-cell lineages characterized by the cytokines produced: Th1 cells secrete predominately IFN-g, Th2 cells release IL-4, IL-5, and IL-13 and Th17 cells typically produce . Although the contribution of DCs for CD4 1 Th-cell polarization is under debate [6], several DC-derived mechanisms have been described to significantly direct Th-cell phenotypes. 3479DCs change their maturation status by upregulating surface expression of MHC class II and costimulatory molecules and by producing a defined set of cytokines to optimally induce distinct Th-cell responses [7][8][9]. Due to their immunostimulatory function, DCs are of particular interest in immunotherapy settings, such as cancer therapy and infectious disease intervention [10,11]. Thus, the Th-cell polarizing profile defined by the maturation signature of DCs is of vital interest. Several membrane markers on DCs and soluble factors secreted by DCs have been described to polarize toward Th2 responses. These include costimulatory molecules such as OX40 [12], , the Notch family member Jagged-2 [14], the cytokine IL-6 [15], or arachidonic acid metabolites such as PGE 2 [16][17][18]. Much less is known about the fac...

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Section: Discussionmentioning

confidence: 73%

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

Pletinckx

Stijlemans²,

Pavlović

et al. 2011

Eur J Immunol

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“…The level of CD83 is correlated with maturation of MDDCs [23,25] while an increase in CD40 or HLA-DR indicate activation of MDDC [25,26]. The mean fluorescence intensity (MFI) of all surface markers (CD83, CD40 and HLA-DR) was significantly increased due to BV CVL (57%, 62% and 52% of LPS respectively) when compared to normal CVL (29%, 22% and 9% of LPS) (Fig.…”

Section: Bv Cvl Increase Activation and Maturation Markers On Mddcmentioning

confidence: 90%

“…Gram negative bacteria contain LPS, whereas gram positive bacteria have no LPS but do contain peptidoglycans (PGN). LPS and PGN can be released from live or dying bacteria at stimulatory levels and have been shown in numerous studies to activate DC through toll like receptors (TLR) [25,26,47]. The two TLR most likely responsible for MDDC activation are TLR2 (activated by PGN) and TLR4 (activated by LPS).…”

Section: Discussionmentioning

confidence: 99%

Dendritic cell activation and maturation induced by mucosal fluid from women with bacterial vaginosis

John

Martinson

Simões

et al. 2007

Clinical Immunology

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Dendritic cells (DC) at mucosal surfaces mature when exposed to "danger" signals such as LPS. Bacterial vaginosis (BV) is a prevalent alteration of the vaginal bacterial flora associated with preterm childbirth and increased risk for HIV acquisition. We examined the effect of mucosal fluid from women with BV or healthy flora on DC function. IL-12, IL-23 and p40 production by monocytederived dendritic cells (MDDC) were all induced by BV samples. Activation/maturation markers HLA-DR, CD40, and CD83 on MDDC incubated with BV CVL were also induced. BV CVL also decreased the endocytic ability of MDDC and increased proliferation of T-cells in allogeneic MLR. Plasmacytoid dendritic cell (pDC) CD86 expression was induced by BV CVL. Healthy flora CVL had little effect in any of the tests. This study suggests that BV, but not healthy flora, affects local dendritic cell function in vivo suggesting a mechanism through which BV affects mucosal immunity.

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“…In addition, an exhaustion of cytokine production has been described and may also influence TH polarization by reverting TH1 cells into TH2 or nonpolarized T cells. 32 These additional signals may be related to the ability of the antigen formulation to induce DC maturation, but dosage and route of presentation (MHC-I versus MHC-II) can also influence TH polarization. [33][34][35][36] Moreover, the amount of CpG sequences in DNA vaccines can influence via toll-like receptors (TLR) whether a TH1 or TH2 T cell response is generated.…”

Section: Discussionmentioning

confidence: 99%

Flt-3 ligand as adjuvant for DNA vaccination augments immune responses but does not skew TH1/TH2 polarization

et al. 2004

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Since transfection of dendritic cells (DC) plays a key role in DNA vaccination, in vivo expansion of DC might be a tool to increase vaccine efficacy. We asked whether Fms-like tyrosine kinase-3 ligand (Flt-3L), a growth factor for DC, can be used as an adjuvant for DNA vaccination. Betagalactosidase (b-gal) was used as a model antigen in C57BL/6 mice. Mice were immunized i.m. with DNA coding for b-gal with or without additional injection of Flt-3L. In both cases, antigen-specific CD4 þ and CD8 þ T cells were detectable after vaccination. Compared with DNA alone, additional administration of Flt-3L led to a significant increase in the antigen-specific proliferative response. However, increased cytotoxicity by T cells was not observed. The cytokines secreted by splenocytes of immunized mice upon in vitro stimulation with antigen had a TH2 profile. Humoral responses against b-gal preferentially consisted of IgG1 antibodies. Analysis of DC from Flt-3L-treated mice revealed an immature phenotype with low or absent expression levels of CD80, CD86 and CD40. We conclude that Flt-3L does not generally skew immune responses towards a TH1 type. More likely, factors determined by the antigen and/or the vaccination procedure itself are crucial for the resulting type of immune response. Flt-3L -under circumstances such as the one we have investigated -can also lead to suppression of TH1 T cell immunity, possibly by expansion of immature/ unactivated DC.

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Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells

Cited by 1,021 publications

References 49 publications

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

Dendritic cell activation and maturation induced by mucosal fluid from women with bacterial vaginosis

Flt-3 ligand as adjuvant for DNA vaccination augments immune responses but does not skew TH1/TH2 polarization

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