Dendritic cells are specialized accessory cells along with TGF-β for the differentiation of Foxp3+ CD4+ regulatory T cells from peripheral Foxp3− precursors

Yamazaki, Sayuri; Bonito, Anthony J.; Špíšek, Radek; Dhodapkar, Madhav V.; Inaba, Kayo; Steinman, Ralph M.

doi:10.1182/blood-2007-05-088831

Cited by 177 publications

(181 citation statements)

References 80 publications

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Section: Partial DC Maturation Stages Induce Th2-cell Responsessupporting

confidence: 86%

“…5A). Nevertheless, DCs matured with TNF, mfVSG, or MiTat1.5 sVSG induced high levels of FoxP3 1 Treg cells in vitro to a similar extent as untreated DCs but superior to LPS-conditioned DCs when exogenous TGF-b was supplied to the culture, further supporting the observation that DCs require TGF-b for the efficient induction of FoxP3 1 Treg cells in vitro as described previously [41].In summary, our data identify Th2-cell differentiation patterns linked to partial DC maturation stages with quantitative differences between pathogen-derived, TLR-dependent VSG antigens, and non-TLR-dependent TNF stimulation in vitro.No induction of FoxP3 1 Treg cells could be observed by any of our DCs in the absence of exogenous TGF-b in vitro.Partially mature DCs show similar priming and Th-cell polarizing capacity in vivo To assess how these DC maturation signatures prime T-cell responses in vivo, we injected differentially matured and OVAloaded DCs together with OVA-specific TCR-transgenic OT-II T cells i.v. and determined proliferation and cytokine production of injected T cells.…”

supporting

confidence: 86%

“…Earlier reports demonstrated that BM-derived DCs efficiently induced CD4 1 CD25 1 FoxP3 1 Treg cells in vitro predominately in the presence of exogenously supplied TGF-b [41]. Indeed, hardly any Treg-cell generation could be detected in the absence of exogenous TGF-b irrespective of the maturation phenotype of the DCs (Supporting Information Fig.…”

Section: Partial DC Maturation Stages Induce Th2-cell Responsesmentioning

confidence: 84%

“…Treg-cell assays were set up as described previously [41] with minor modifications. Briefly, purified CD4 1 CD25 À OT-II T cells (2 Â 10 4 ) were cultured with day 8 BM-DCs (6 Â 10 3 ) matured with various maturation stimuli for 4-6 h prior to coculture and 100 ng/mL OVA-peptide 327-339 (Activotec) in 96-well roundbottom plates (Greiner Bio-One).…”

Section: In Vitro Treg-cell Conversion Assaymentioning

confidence: 99%

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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: Partial DC Maturation Stages Induce Th2-cell Responsessupporting

confidence: 86%

supporting

confidence: 86%

Section: Partial DC Maturation Stages Induce Th2-cell Responsesmentioning

confidence: 84%

Section: In Vitro Treg-cell Conversion Assaymentioning

confidence: 99%

See 2 more Smart Citations

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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“…In agreement with this, importantly, we showed that such a defect in the MRL/lpr DC function could be fully restored by exogenous IL-2. IL-2 has been shown to be essential in the Treg induction by DC in various systems, both in an antigen-specific and nonspecific manner [50][51][52], although different findings were also reported [53]. It remains to be determined as to whether the T cells upon stimulation by the DC [51], or DC themselves, or both of the cell types together, could be the direct source of IL-2.…”

Section: Discussionmentioning

confidence: 95%

Immunological mechanisms and clinical implications of regulatory T cell deficiency in a systemic autoimmune disorder: Roles of IL‐2 versus IL‐15

et al. 2008

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Regulatory T cell deficiency is evident in patients with lupus, but the casual relationship and underlying mechanism leading to Treg deficiency are unclear. We analyzed the Treg profile, induction and functions of Treg in a lupus mouse model. A characteristic agedependent biphasic change of Treg frequency was observed in the MRL/lpr mice, which developed a spontaneous lupus-like disease. After an early increase, Treg frequency in the peripheral lymphoid organs rapidly declined with age. Functionally, Treg from both young and old MRL/lpr mice were fully competent in suppressing the wild-type MRL/+ T effector cell (Teff) responses. Adoptive transfer of MRL/+ Treg markedly suppressed clinical disease in the MRL/lpr mice. We demonstrated that the reduced Treg frequency was a result of insufficient peripheral Treg expansion due to defective MRL/lpr Teff in IL-2 production, and the associated defects in dendritic cells, which could be fully restored by exogenous IL-2. In the absence of IL-2, MRL/lpr Teff but not MRL/lpr Treg were highly responsive to IL-15 and could expand rapidly due to enhanced IL-15R expression and IL-15 synthesis. These findings thus provide a clear causal relationship and immunological mechanism underlying Treg deficiency and systemic autoimmunity.

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Molecular Mimicry

Cunningham¹

2009

Encyclopedia of Life Sciences

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Molecular mimicry is structural, functional or immunological similarities shared between macromolecules found on infectious pathogens and in host tissues. Molecular mimicry plays an important role in immune responses to infection and in autoimmune diseases. Infection may induce autoimmune responses which attack and destroy body tissues or organs. Normally, the body is tolerant to self‐antigens which are present in individual tissues. In autoimmune disease, tolerance is abrogated to self‐antigens, and tissues or organs are destroyed by the immune system. Molecular mimicry of a self‐antigen by an infectious pathogen, such as bacteria and viruses, may trigger autoimmune disease due to a crossreactive immune response against the infection. Crossreactive antigen–antibody and T cell–antigen reactions are used to identify the mimicking macromolecules on the pathogen and in tissues or organs. These parameters define the concept of molecular mimicry. Key Concepts: There are three types of mimicry. Immunological mimicry between dissimilar epitopes on chemically different molecules has changed the concept that an antibody molecule must recognize only a single antigenic epitope. Although molecular mimicry was once thought by immunologists to be a ‘phenomenon’ or ‘nonspecific immune reaction’, mimicry is now considered to be a part of the normal immune system and plays an important role in protection against pathogens. Microbial infections may activate the immune system and lead to a loss of immune tolerance which could allow expansion of high avidity crossreactive B‐ or T‐cell clones which through molecular mimicry may lead to autoimmune disease. Mimicry has been shown to lead to the induction of autoantibodies which alter signalling in cells.

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Dendritic cells are specialized accessory cells along with TGF-β for the differentiation of Foxp3+ CD4+ regulatory T cells from peripheral Foxp3− precursors

Cited by 177 publications

References 80 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

Immunological mechanisms and clinical implications of regulatory T cell deficiency in a systemic autoimmune disorder: Roles of IL‐2 versus IL‐15

Molecular Mimicry

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