Instruction of Distinct CD4 T Helper Cell Fates by Different Notch Ligands on Antigen-Presenting Cells

Amsen, Derk; Blander, J. Magarian; Lee, Gap Ryol; Tanigaki, Kenji; Honjo, Tasuku; Flavell, Richard A.

doi:10.1016/s0092-8674(04)00451-9

Cited by 797 publications

(1,018 citation statements)

References 79 publications

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“…Also, a pathway involving the Notch family of ligands, which seems to be cytokine independent, has been described. Delta induces Th1 differentiation, while Jagged induces the alternate Th2 pathway [19].…”

Section: Discussionmentioning

confidence: 99%

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Pertussis toxin-induced cytokine differentiation and clonal expansion of T cells is mediated predominantly via costimulation

Denkinger

Forsthuber

2007

Cellular Immunology

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Pertussis toxin (PTX) has potent immunologic adjuvant activity in vivo and concomitantly enhances both T helper type (Th) 1 and Th2 cytokine responses. The PTX-induced enhancement of Th1 and Th2 immunity is mediated via the activation of antigen presenting cells (APCs), but the underlying mechanism is not known.Here we asked whether the adjuvant activity of PTX on T cell immunity was mediated by cytokines and/or costimulatory signals.The results show that in vivo blockade of CD28-CD80/86 costimulation essentially abrogated PTXmediated enhancement of antigen-specific Th1 and Th2 responses. Blockade of CD40L-CD40 interactions was less efficient in inhibiting PTX-mediated enhancement of Th1 and Th2 responses. In contrast, the adjuvant activity of PTX was not mediated via cytokines, because neither Th1 nor Th2 responses were substantially impaired in mice deficient for IL-12, IFN-γ, IL-4, IL-5, or IL-6.Collectively, the data suggest that PTX mediates its adjuvant effects on T cell cytokine differentiation and clonal expansion via the modulation of costimulatory molecules on APCs. Understanding the costimulatory pathways targeted by PTX could lead to the design of novel adjuvants that selectively induce Th1 or Th2 immunity.

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Section: Discussionmentioning

confidence: 99%

“…C3H-HeJ-mice, which carry a mutation in the toll-like receptor 4 gene, Tlr4 Lps-d , may be useful to address PTX effects on the TLR4 pathway in our model. Alternatively, a model involving the Notch family with the subsequent activation of T cells has to be considered [19].…”

Section: Discussionmentioning

confidence: 99%

Pertussis toxin-induced cytokine differentiation and clonal expansion of T cells is mediated predominantly via costimulation

Denkinger

Forsthuber

2007

Cellular Immunology

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“…cDNA was synthesized using Superscript III Reverse Transcriptase (Invitrogen). Quantitative expression of the Notch ligands Jagged1, Jagged2, and Delta4 was determined with a Biorad iCycler iQ (Biorad) using primers described previously [14]. Real-Time PCR was run for 40 cycles and performed in 25 mL volume containing 0.5 Â Absolute QPCR SYBR Green mix (Thermo Fisher Scientific), 1 mL of 1:10 diluted cDNA sample and 0.2 mM of each primer.…”

Section: Real-time Pcr Of Notch Ligandsmentioning

confidence: 99%

“…These include costimulatory molecules such as OX40 [12], ICOS-L [13], 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 factors that induce such Th2-instructing DC.…”

Section: Introductionmentioning

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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“…Later studies showed that Notch was also involved in mammalian differentiation processes including those governing the development of the immune system (19). The latter included evidence for a role of Notch signaling in the intrathymic differentiation of T cells (20 -22) as well as Th cell development in the periphery (23)(24)(25)(26)(27). Notch is, like TGF-␤, an evolutionarily conserved molecule but, unlike TGF-␤, is a type I transmembrane receptor rather than a receptor ligand.…”

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confidence: 99%

Notch1 Signaling and Regulatory T Cell Function

Asano

Watanabe

Kitani

et al. 2008

The Journal of Immunology

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Previous studies have shown that the Notch1 and TGF-β signaling pathways are mutually re-enforcing. Given recent evidence that regulatory T cell (Treg) effector function is mediated by TGF-β signaling, we investigated whether Notch1 signaling also participated in Treg effector function. Initial studies showed that Notch1 ligands, particularly Jagged1, are present on Tregs and that, indeed, blockade of Notch1 signaling with an anti-Jagged1 or a blocking anti-Notch1 Ab inhibits Treg suppressor function in vitro. We then showed that a signaling component generated by Notch1 activation (Notch1 intracellular domain) of dendritic cells physically interacts with a signaling component generated by TGF-β signaling (pSmad3). Furthermore, this interaction has functional downstream effects because over-expression of Notch1 intracellular domain facilitates pSmad3 translocation to the nucleus and enhances pSmad3 transcriptional activity of a Smad-sensitive promoter linked to a luciferase reporter. Finally, we showed that blockade of TGF-β signaling and Notch signaling did not have additive inhibitory effects on Treg suppressor function. These results are consistent with the conclusion that Notch1 signaling facilitates TGF-β-mediated effector function of Tregs.

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Instruction of Distinct CD4 T Helper Cell Fates by Different Notch Ligands on Antigen-Presenting Cells

Cited by 797 publications

References 79 publications

Pertussis toxin-induced cytokine differentiation and clonal expansion of T cells is mediated predominantly via costimulation

Pertussis toxin-induced cytokine differentiation and clonal expansion of T cells is mediated predominantly via costimulation

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

Notch1 Signaling and Regulatory T Cell Function

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