Essential role of Notch signaling in effector memory CD8+ T cell-mediated airway hyperresponsiveness and inflammation.
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.
Okamoto
Masakazu
M
Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.
Takeda
Katsuyuki
K
Joetham
Anthony
A
Ohnishi
Hiroshi
H
Matsuda
Hiroyuki
H
Swasey
Christina H
CH
Swanson
Bradley J
BJ
Yasutomo
Koji
K
Dakhama
Azzeddine
A
Gelfand
Erwin W
EW
D019264:Adoptive Transfer; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000503:physiopathology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000276:immunology / Q000502:physiology*; D007156:Immunologic Memory; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D010047:Ovalbumin / Q000276:immunology; D012313:RNA / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D051880:Receptors, Notch / Q000502:physiology*
D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D051880:Receptors, Notch; D012313:RNA; D010047:Ovalbumin