T-bet inhibits both TH2 cell-mediated eosinophil recruitment and TH17 cell-mediated neutrophil recruitment into the airways
T-bet inhibits both TH2 cell-mediated eosinophil recruitment and TH17 cell-mediated neutrophil recruitment into the airways
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DOI：
10.1016/j.jaci.2006.12.643
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发表时间：
2007-03-01
影响因子：
14.2
通讯作者：
Nakajima, Hiroshi
中科院分区：
文献类型：
--
作者：
Fujiwara, Michio;Hirose, Koichi;Nakajima, Hiroshi
背景：之前的研究表明，缺乏 T-bet（T(H)1 细胞分化的关键转录因子）的小鼠会自发出现气道炎症，伴有强烈的嗜酸性粒细胞浸润。然而，T-bet 介导的抑制过敏性气道炎症的机制仍不清楚。目的：确定 T-bet 在抗原诱导的过敏性气道炎症中的调节作用。方法：我们使用 BALB/c 背景下未发生自发性过敏反应的 T-bet(-/-) 小鼠，研究了 T-bet 在抗原诱导的过敏性气道炎症中的作用。 气道炎症。我们还通过过继转移实验研究了 CD4(+) T 细胞的 T-bet 表达在气道炎症中的作用。结果：我们发现 T-bet-/- 小鼠气道中抗原诱导的嗜酸性粒细胞募集、杯状细胞增生和 T(H)2 细胞因子产生增强。然而，在缺乏信号转导子和转录激活子6（STAT6）的情况下，T-bet缺陷不能诱导抗原诱导的嗜酸性粒细胞性气道炎症。将 T-bet(-/-) 或 T-bet(+/+) CD4(+) T 细胞过继转移至 T-bet(-/-)Rag-2(-/-) 小鼠体内表明，CD4+ T 细胞中 T-bet 的表达对于抑制抗原诱导的嗜酸性粒细胞气道炎症至关重要。有趣的是，抗原诱导的中性粒细胞在气道中的募集也得到增强。 T-bet-/- 小鼠。此外，T-bet(-/-) CD4(+) T 细胞优先分化为产生 IL-17 的细胞，介导中性粒细胞气道炎症。结论：T-bet 抑制 TH2 细胞介导的嗜酸性粒细胞炎症和 TH17 细胞介导的中性粒细胞气道炎症。临床意义：T-bet 功能障碍可能与严重哮喘的发病机制有关，其中气道中中性粒细胞和嗜酸性粒细胞的积聚是疾病的标志。
Background: Previous studies have shown that mice lacking T-bet, a critical transcription factor for T(H)1 cell differentiation, spontaneously develop airway inflammation with intense eosinophil infiltrates. However, the mechanism underlying T-bet-mediated inhibition of allergic airway inflammation is still unknown.Objective: To determine the regulatory role of T-bet in antigen-induced allergic airway inflammation.Methods: We examined the role of T-bet in antigen-induced allergic airway inflammation using T-bet(-/-) mice on a BALB/c background that did not develop spontaneous airway inflammation. We also examined the role of T-bet expression of CD4(+) T cells in airway inflammation by adoptive transfer experiments.Results: We found that antigen-induced eosinophil recruitment, goblet cell hyperplasia, and T(H)2 cytokine production in the airways were enhanced in T-bet-/- mice. However, in the absence of signal transducer and activator of transcription 6 (STAT6), T-bet deficiency could not induce the antigen-induced eosinophilic airway inflammation. Adoptive transfer of T-bet(-/-) or T-bet(+/+) CD4(+) T cells to T-bet(-/-)Rag-2(-/-) mice revealed that the expression of T-bet in CD4+ T cells was vital for the inhibition of antigen-induced eosinophilic airway inflammation.Interestingly, antigen-induced neutrophil recruitment in the airways was also enhanced in T-bet-/- mice. Moreover, T-bet(-/-) CD4(+) T cells preferentially differentiated into IL-17-producing cells that mediated neutrophilic airway inflammation.Conclusion: T-bet inhibits both TH2 cell-mediated eosinophilic inflammation and TH17 cell-mediated neutrophilic inflammation in the airways. Clinical implications: The dysfunction of T-bet may be involved in the pathogenesis of severe asthma, in which accumulation of neutrophils as well as eosinophils in the airways is a hallmark of disease.