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

Masakazu Okamoto1, Katsuyuki Takeda, Anthony Joetham

  • 1Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.

The Journal of Experimental Medicine
|April 23, 2008
PubMed

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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