Okamoto Masakazu, Takeda Katsuyuki, Joetham Anthony, Ohnishi Hiroshi, Matsuda Hiroyuki, Swasey Christina H, Swanson Bradley J, Yasutomo Koji, Dakhama Azzeddine, Gelfand Erwin W
Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.
J Exp Med. 2008 May 12;205(5):1087-97. doi: 10.1084/jem.20072200. Epub 2008 Apr 21.
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.
体内致敏的CD8(+) T细胞或体外产生的效应记忆CD8(+) T（T(EFF)）细胞的过继转移可恢复CD8缺陷（CD8(-/-)）小鼠的气道高反应性（AHR）和气道炎症。通过检测转录水平发现，与中枢记忆CD8(+) T细胞相比，T(EFF)细胞中Notch1有强烈诱导。用γ-分泌酶抑制剂（GSI）处理T(EFF)细胞可强烈抑制这些细胞中的Notch信号，过继转移后，经GSI处理的T(EFF)细胞在致敏和激发的受体CD8(-/-)小鼠中无法恢复AHR和气道炎症，在受体野生型（WT）小鼠中也无法增强这些反应。GSI的这些作用还与T(EFF)细胞中Notch配体Delta1的表达增加有关。用Delta1-Fc处理致敏和激发的WT小鼠会导致AHR和气道炎症减轻，同时支气管肺泡灌洗液中干扰素γ水平升高。这些结果表明，由于Notch受体激活受到抑制以及Notch配体Delta1上调，Notch在使T细胞反应从辅助性T（Th）2表型向Th1表型转变中发挥作用。这些数据首次表明Notch在CD8(+) T细胞介导的AHR和气道炎症发展的激发阶段具有功能作用，并确定Delta1是过敏性气道炎症的重要调节因子。
