The Journal of Experimental Medicine
Torrey Pines Biolabs
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
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.
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental Material Index
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JEM
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via CrossRef
Google Scholar
Right arrow Articles by Okamoto, M.
Right arrow Articles by Gelfand, E. W.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Okamoto, M.
Right arrow Articles by Gelfand, E. W.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

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.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?




  Home | Help | Feedback | Subscriptions | Archive | Search
TABLE OF CONTENTS