Essential role of Notch signaling in effector memory CD8+ T cell–mediated airway hyperresponsiveness and inflammation
In: The Journal of Experimental Medicine, Jg. 205 (2008), Heft 5, S. 1087-1097
Online
unknown
Zugriff:
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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Essential role of Notch signaling in effector memory CD8+ T cell–mediated airway hyperresponsiveness and inflammation
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Autor/in / Beteiligte Person: | Matsuda, Hiroyuki ; Gelfand, Erwin W. ; Yasutomo, Koji ; Takeda, Katsuyuki ; Okamoto, Masakazu ; Dakhama, Azzeddine ; Ohnishi, Hiroshi ; Joetham, Anthony ; Swasey, Christina H. ; Swanson, Bradley J. |
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Zeitschrift: | The Journal of Experimental Medicine, Jg. 205 (2008), Heft 5, S. 1087-1097 |
Veröffentlichung: | The Rockefeller University Press, 2008 |
Medientyp: | unknown |
ISSN: | 1540-9538 (print) ; 0022-1007 (print) |
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