The Journal of Experimental Medicine
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Published online April 21, 2008
doi:10.1084/jem.20072200
The Journal of Experimental Medicine, Vol. 205, No. 5, 1087-1097
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Okamoto et al.
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ARTICLE

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

Masakazu Okamoto1, Katsuyuki Takeda1, Anthony Joetham1, Hiroshi Ohnishi1, Hiroyuki Matsuda1, Christina H. Swasey1, Bradley J. Swanson2, Koji Yasutomo3, Azzeddine Dakhama1, and Erwin W. Gelfand1

1 Division of Cell Biology, Department of Pediatrics, and the 2 Integrated Department of Immunology, National Jewish Medical and Research Center, Denver, CO 80206
3 Department of Immunology and Parasitology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan

CORRESPONDENCE Erwin W. Gelfand: gelfande{at}njc.org

Adoptive transfer of in vivo–primed CD8+ T cells or in vitro–generated effector memory CD8+ T (TEFF) cells restores airway hyperresponsiveness (AHR) and airway inflammation in CD8-deficient (CD8–/–) mice. Examining transcription levels, there was a strong induction of Notch1 in TEFF cells compared with central memory CD8+ T cells. Treatment of TEFF cells with a {gamma}-secretase inhibitor (GSI) strongly inhibited Notch signaling in these cells, and after adoptive transfer, GSI-treated TEFF 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 TEFF 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.

Abbreviations used: AHR, airway hyperresponsiveness; BAL, bronchoalveolar lavage; GSI, {gamma}-secretase inhibitor; MCh, methacholine; MNC, mononuclear cell; NICD, Notch intracellular domain; RL, lung resistance; TCM, central memory CD8+ T; TEFF, effector memory CD8+ T.


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