Protective role of nuclear factor of activated T cells 2 in CD8+ long-lived memory T cells in an allergy model
Protective role of nuclear factor of activated T cells 2 in CD8+ long-lived memory T cells in an allergy model
复制标题
DOI：
10.1016/j.jaci.2007.12.1172
复制
发表时间：
2008-04-01
影响因子：
14.2
通讯作者：
Finotto, Susetta
中科院分区：
文献类型：
--
作者：
Karwot, Roman;Maxeiner, Joachim H.;Finotto, Susetta
背景：记忆T细胞释放和控制的细胞因子的转录调控还不是很清楚。目的：了解激活T细胞转录因子2(NFATc2)在实验性变态反应性哮喘中的作用。方法：采用变态反应性哮喘小鼠模型和荧光激活的分选细胞过继转移模型。结果：NFATc2缺失小鼠的气道高反应性(AHR)、重塑和血清IgE水平在卵蛋白致敏中的作用。这种表型与CD8(+)CD122(-)T细胞在呼吸道产生干扰素-γ的缺陷有关。NFATc2(-/-)小鼠这种表型的起源与肺CD8(+)CD122(+)(IL-2Rβ链)CD127(Hi)(IL-7受体[R]阿尔法链(+))长寿命记忆细胞的扩大有关。过继转移卵清蛋白特异性CD8(+)NFATc2((-/-))T细胞可增强NFATc2((-/-))CD4(+)T细胞在免疫缺陷小鼠体内产生的AHR，增加IL-17，减少重组小鼠产生的干扰素-γ。记忆性CD8(+)CD122(+)IL-7R(高)T细胞群的耗尽纠正了肺NFATc2((-/-))CD8(+)CD122(+)细胞产生干扰素-γ的缺陷，并消除了在NFATc2((-/-))CD8(+)T细胞重组小鼠中观察到的升高的AHR。结论：综上所述，我们的结果提示，长寿命记忆CD8(+)T细胞表达NFATc2控制肺CD8(+)T细胞产生IL-2和干扰素-γ，然后在过敏原攻击期间限制T(H)17和T(H)2在呼吸道中的发育。
Background: The transcriptional regulation of cytokines released and controlled by memory T cells is not well understood. Defective IFN-gamma production in allergic asthma correlates in human beings with the risk of wheezing in childhood.Objective: To understand the role of the transcription factor nuclear factor of activated T cells 2 (NFATc2) in memory and effector T cells in the airways in experimental allergic asthma.Methods: We used murine models of allergic asthma and adoptive cell transfer of fluorescence-activated sorted cells in a disease model.Results: Mice lacking NFATc2 developed an increase in airway hyperresponsiveness (AHR), remodeling, and serum IgE levels on ovalbumin sensitization. This phenotype was associated with CD8(+)CD122(-) T cells deficient in IFN-gamma production in the airways. The origin of this phenotype in NFATc2((-/-)) mice was related to an expanded population of lung CD8(+)CD122(+) (IL-2R beta chain) CD127(hi) (IL-7 receptor [R] alpha chain(+)) long-lived memory cells. Adoptive transfer of ovalbumin-specific CD8(+) NFATc2((-/-)) T cells enhanced the AHR generated by NFATc2((-/-)) CD4(+) T cells in immunodeficient mice, increased IL-17, and reduced IFN-gamma production in the reconstituted mice. Depletion of the memory CD8(+)CD122(+)IL-7R(high) T-cell population corrected the defect in IFN-gamma production by lung NFATc2((-/-)) CD8(+)CD122(+) cells and abrogated the increased AHR observed in NFATc2((-/-)) CD8(+) T-cell-reconstituted mice with a severe combined immunodeficiency disorder.Conclusion: Taken together, our results suggest that NFATc2 expression in long-lived memory CD8(+) T cells controls IL-2 and IFN-gamma production in lung CD8(+) T cells, which then limits T(H)17 and T(H)2 development in the airways during allergen challenge.