Flexibility of Mouse Classical and Plasmacytoid-derived Dendritic Cells in Directing T Helper Type 1 and 2 Cell Development

Boonstra, André; Asselin‐Paturel, Carine; Gilliet, Michel; Crain, Chad; Trinchieri, Giorgio; Liu, Yongjun; O’Garra, Anne

doi:10.1084/jem.20021908

Cited by 496 publications

(476 citation statements)

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“…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. 33 It appears that the amount of immunostimulatory CpG sequences in our plasmid DNA is not sufficient to induce TH1 polarization.…”

Section: Discussionmentioning

confidence: 99%

“…[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. 33 It appears that the amount of immunostimulatory CpG sequences in our plasmid DNA is not sufficient to induce TH1 polarization. Indeed, coadministration of antigen with immunostimulatory, CpG-rich DNA and Flt-3L can induce therapeutic immunity.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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“…This further illustrates the dichotomy between epitopes bound by different isotypes, and suggests that heatdenatured allergens could also be useful in SIT in humans. Moreover, it allows the use of higher therapeutic doses, which per se is known to promote Th1 immune responses [40,41] and to be favourable in combating allergic immunopathology [15,16].In conclusion, heat-denatured allergen extracts show reduced IgE binding and therefore would increase the safety and tolerability of SIT. Yet surprisingly, heat denaturation of allergen extracts enhanced production of the Th1-dependent IgG2a subclass, which worked therapeutically in allergic mice.…”

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Heat denaturation, a simple method to improve the immunotherapeutic potential of allergens

et al. 2005

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Allergen-specific immunotherapy (SIT) leads to a long-term amelioration of IgE-and Th2-mediated allergic diseases. However, SIT efficiency is low, with years of treatment along with frequent allergic side effects. The goal of this study was to reduce the side effects by destroying IgE-binding epitopes, i.e. by heat-denaturation, while preserving the therapeutic effect. Mice were immunised with bee venom, birch pollen, grass pollen or cat hair allergens, or with ovalbumin. Heat-denatured allergens bound less IgE but enhanced Th1-dependent IgG2a production as measured by ELISA. The strong IgG2a antibody responses also prevented allergic anaphylaxis in mice, as measured by body temperature drop after a challenge with a high allergen dose. We found that optimal heat-denaturation of allergens left a small proportion in the native conformation to sufficiently stimulate B cells, while non-B cell-mediated effects were probably amplified. The enhanced immunogenicity of heat-denatured allergens is likely explained by enhanced antigen presentation to T cells due to the particulate nature of heat-denatured proteins. This enables Th1 skewing of the immune response with strong production of IgG2a in mice. Therefore, heat-denaturation represents probably the simplest way to enhance the efficiency of SIT while reducing its side effects. IntroductionIgE-mediated type I hypersensitivity is characterised by prominent activity of mast cells, eosinophils, T helper type 2 (Th2) cells and cytokine actions. Allergenspecific immunotherapy (SIT) leads to long-term amelioration of allergic symptoms and is therefore recommended as a first-line therapy for allergies [1]. During SIT, gradually increasing allergen doses are subcutaneously administered until a maintenance dose is reached, and then treatment continues for 3-5 years. Such lengthy treatment, requiring 30-80 allergen injections, is very costly [2]. Also, SIT frequently causes adverse events due to the interaction of specific IgE with the injected allergen. These adverse events frequently include a local reaction at the site of allergen injection, but also life-threatening systemic reactions such as asthma and anaphylaxis. This is why the administered allergen doses must be kept relatively low, which unfortunately favours Th2 immune responses in contrast to higher doses [3][4][5].Several strategies have been developed to tackle the problems of SIT, i.e. to reduce its side effects and to enhance its immunogenicity. One strategy is to replace the currently used aluminium salts, which have Th2-polarizing properties, with novel adjuvants such as Tolllike receptor ligands [6,7] that trigger Th1 responses. Another strategy is to increase safety and tolerability of SIT by injecting the allergen in a form that is not recognised by IgE, such as naked DNA vaccines Heat-denaturation is well known to reduce the reactogenicity of allergens with IgE, as cooked foods are usually well or better tolerated by allergic individuals [24][25][26]. In this study, we tested whether this very simple strate...

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“…However, since these quantitative changes led to qualitatively different Th1 or Th2-cell polarization, this may reflect another DC-based aspect of the ''strength of signal'' theory where peptide titrations and affinities heavily influenced the Th-cell skewing potential [59,60]. The peptide dose dependency has been shown to be independent of the DC subtype but strong LPS or CpG stimulation clearly shifted toward Th1-cell [61]. As a mechanism how this could be regulated, others proposed that weak T-cell stimulation prevents CD40L upregulation, which in turn was required to trigger CD40 on DCs for their IL-12 production and Th1-cell immunity [62].…”

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confidence: 99%

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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Flexibility of Mouse Classical and Plasmacytoid-derived Dendritic Cells in Directing T Helper Type 1 and 2 Cell Development

Cited by 496 publications

References 55 publications

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

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

Heat denaturation, a simple method to improve the immunotherapeutic potential of allergens

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

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