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Essential role of Notch signaling in effector memory CD8+ T cell-mediated airway hyperresponsiveness and inflammation.

Okamoto M, Takeda K, Joetham A, Ohnishi H, Matsuda H, Swasey CH, Swanson BJ, Yasutomo K, Dakhama A, Gelfand EW - J. Exp. Med. (2008)

Bottom Line: Examining transcription levels, there was a strong induction of Notch1 in T(EFF) cells compared with central memory CD8(+) T cells.These effects of GSI were also associated with increased expression of the Notch ligand Delta1 in T(EFF) cells.These results demonstrate a role for Notch in skewing the T cell response from a T helper (Th)2 to a Th1 phenotype as a consequence of the inhibition of Notch receptor activation and the up-regulation of the Notch ligand Delta1.

View Article: PubMed Central - PubMed

Affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.

ABSTRACT
Adoptive transfer of in vivo-primed CD8(+) T cells or in vitro-generated effector memory CD8(+) T (T(EFF)) cells restores airway hyperresponsiveness (AHR) and airway inflammation in CD8-deficient (CD8(-/-)) mice. Examining transcription levels, there was a strong induction of Notch1 in T(EFF) cells compared with central memory CD8(+) T cells. Treatment of T(EFF) cells with a gamma-secretase inhibitor (GSI) strongly inhibited Notch signaling in these cells, and after adoptive transfer, GSI-treated T(EFF) cells failed to restore AHR and airway inflammation in sensitized and challenged recipient CD8(-/-) mice, or to enhance these responses in recipient wild-type (WT) mice. These effects of GSI were also associated with increased expression of the Notch ligand Delta1 in T(EFF) cells. Treatment of sensitized and challenged WT mice with Delta1-Fc resulted in decreased AHR and airway inflammation accompanied by higher levels of interferon gamma in bronchoalveolar lavage fluid. These results demonstrate a role for Notch in skewing the T cell response from a T helper (Th)2 to a Th1 phenotype as a consequence of the inhibition of Notch receptor activation and the up-regulation of the Notch ligand Delta1. These data are the first to show a functional role for Notch in the challenge phase of CD8(+) T cell-mediated development of AHR and airway inflammation, and identify Delta1 as an important regulator of allergic airway inflammation.

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Allergen-induced AHR and airway inflammation are prevented by administration of Delta1-Fc. Secondary challenged (OVA/OVA/OVA) or control (OVA/OVA/PBS) WT mice received Delta1-Fc or human IgG. (A) Experimental protocol, (B) AHR, (C) cell composition in BAL fluid, (D) BAL cytokine levels, and (E) number of IFN-γ+–producing CD4+ or CD8+ T cells in the lung. The results for each group are expressed as the mean ± SEM (n = 8 in each group). #, significant difference (P < 0.05) between Delta1-Fc–treated secondary challenged mice and human IgG–treated secondary challenged mice or control mice.
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fig5: Allergen-induced AHR and airway inflammation are prevented by administration of Delta1-Fc. Secondary challenged (OVA/OVA/OVA) or control (OVA/OVA/PBS) WT mice received Delta1-Fc or human IgG. (A) Experimental protocol, (B) AHR, (C) cell composition in BAL fluid, (D) BAL cytokine levels, and (E) number of IFN-γ+–producing CD4+ or CD8+ T cells in the lung. The results for each group are expressed as the mean ± SEM (n = 8 in each group). #, significant difference (P < 0.05) between Delta1-Fc–treated secondary challenged mice and human IgG–treated secondary challenged mice or control mice.

Mentions: To directly test whether Delta1 regulates AHR and airway inflammation, sensitized and challenged WT mice were treated with Delta1-Fc or human IgG as a control before secondary OVA challenge (OVA/OVA/OVA) (Fig. 5 A). Administration of Delta1-Fc markedly reduced AHR compared with administration of (control) human IgG in response to secondary allergen challenge (Fig. 5 B). Neither Delta1-Fc nor human IgG altered the response in control mice (OVA/OVA/PBS). In parallel, administration of Delta1-Fc to secondary challenged mice markedly reduced the numbers of eosinophils and levels of IL-13 in the BAL fluid without affecting these responses in controls (Fig. 5, C and D).


Essential role of Notch signaling in effector memory CD8+ T cell-mediated airway hyperresponsiveness and inflammation.

Okamoto M, Takeda K, Joetham A, Ohnishi H, Matsuda H, Swasey CH, Swanson BJ, Yasutomo K, Dakhama A, Gelfand EW - J. Exp. Med. (2008)

Allergen-induced AHR and airway inflammation are prevented by administration of Delta1-Fc. Secondary challenged (OVA/OVA/OVA) or control (OVA/OVA/PBS) WT mice received Delta1-Fc or human IgG. (A) Experimental protocol, (B) AHR, (C) cell composition in BAL fluid, (D) BAL cytokine levels, and (E) number of IFN-γ+–producing CD4+ or CD8+ T cells in the lung. The results for each group are expressed as the mean ± SEM (n = 8 in each group). #, significant difference (P < 0.05) between Delta1-Fc–treated secondary challenged mice and human IgG–treated secondary challenged mice or control mice.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2373841&req=5

fig5: Allergen-induced AHR and airway inflammation are prevented by administration of Delta1-Fc. Secondary challenged (OVA/OVA/OVA) or control (OVA/OVA/PBS) WT mice received Delta1-Fc or human IgG. (A) Experimental protocol, (B) AHR, (C) cell composition in BAL fluid, (D) BAL cytokine levels, and (E) number of IFN-γ+–producing CD4+ or CD8+ T cells in the lung. The results for each group are expressed as the mean ± SEM (n = 8 in each group). #, significant difference (P < 0.05) between Delta1-Fc–treated secondary challenged mice and human IgG–treated secondary challenged mice or control mice.
Mentions: To directly test whether Delta1 regulates AHR and airway inflammation, sensitized and challenged WT mice were treated with Delta1-Fc or human IgG as a control before secondary OVA challenge (OVA/OVA/OVA) (Fig. 5 A). Administration of Delta1-Fc markedly reduced AHR compared with administration of (control) human IgG in response to secondary allergen challenge (Fig. 5 B). Neither Delta1-Fc nor human IgG altered the response in control mice (OVA/OVA/PBS). In parallel, administration of Delta1-Fc to secondary challenged mice markedly reduced the numbers of eosinophils and levels of IL-13 in the BAL fluid without affecting these responses in controls (Fig. 5, C and D).

Bottom Line: Examining transcription levels, there was a strong induction of Notch1 in T(EFF) cells compared with central memory CD8(+) T cells.These effects of GSI were also associated with increased expression of the Notch ligand Delta1 in T(EFF) cells.These results demonstrate a role for Notch in skewing the T cell response from a T helper (Th)2 to a Th1 phenotype as a consequence of the inhibition of Notch receptor activation and the up-regulation of the Notch ligand Delta1.

View Article: PubMed Central - PubMed

Affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.

ABSTRACT
Adoptive transfer of in vivo-primed CD8(+) T cells or in vitro-generated effector memory CD8(+) T (T(EFF)) cells restores airway hyperresponsiveness (AHR) and airway inflammation in CD8-deficient (CD8(-/-)) mice. Examining transcription levels, there was a strong induction of Notch1 in T(EFF) cells compared with central memory CD8(+) T cells. Treatment of T(EFF) cells with a gamma-secretase inhibitor (GSI) strongly inhibited Notch signaling in these cells, and after adoptive transfer, GSI-treated T(EFF) cells failed to restore AHR and airway inflammation in sensitized and challenged recipient CD8(-/-) mice, or to enhance these responses in recipient wild-type (WT) mice. These effects of GSI were also associated with increased expression of the Notch ligand Delta1 in T(EFF) cells. Treatment of sensitized and challenged WT mice with Delta1-Fc resulted in decreased AHR and airway inflammation accompanied by higher levels of interferon gamma in bronchoalveolar lavage fluid. These results demonstrate a role for Notch in skewing the T cell response from a T helper (Th)2 to a Th1 phenotype as a consequence of the inhibition of Notch receptor activation and the up-regulation of the Notch ligand Delta1. These data are the first to show a functional role for Notch in the challenge phase of CD8(+) T cell-mediated development of AHR and airway inflammation, and identify Delta1 as an important regulator of allergic airway inflammation.

Show MeSH
Related in: MedlinePlus