Malaghan Institute of Medical Research, 6012 Wellington, New Zealand.
J Immunol. 2012 Feb 15;188(4):1734-41. doi: 10.4049/jimmunol.1102699. Epub 2012 Jan 16.
Allergen-specific CTL have a protective effect on allergic airway inflammation, a function thought to be mediated by cytokines, especially IFN-γ. However, the contribution of cytotoxic function to this protective effect has not been investigated. We examined the contribution of cytotoxic function to the therapeutic effect of allergen-specific CTL in allergic airway inflammation. We used a murine model of allergic airway inflammation in which mice were sensitized to OVA and then challenged with the same Ag via the intranasal route. CTL were elicited in these mice by immunization with dendritic cells (DC) or by adoptive transfer of in vitro-activated CD8(+) T cells. Hallmark features of allergic asthma, such as infiltration of eosinophils in the bronchoalveolar lavage fluid and mucus production, were assessed. Suppression of allergic airway inflammation by allergen-specific CTL was critically dependent on the expression of perforin, a key component of the cytotoxic machinery. Both perforin-sufficient and perforin-deficient allergen-specific CTL were recovered from the lungs of allergen-sensitized mice and upregulated CD69 expression and secreted the cytokines IFN-γ and TNF-α upon intranasal allergen challenge. However, only perforin-sufficient CTL inhibited eosinophil infiltration in the airway, mucus production, and cytokine accumulation in the bronchoalveolar lavage fluid. Treatment with allergen-specific CTL, but not their perforin-deficient counterparts, was also associated with a decrease in the number of DC in the mediastinal lymph node. Our data suggest that the cytotoxic function of allergen-specific CD8(+) T cells is critical to their ability to moderate allergic airway inflammation.
过敏原特异性 CTL 对过敏性气道炎症具有保护作用，这种功能被认为是由细胞因子介导的，尤其是 IFN-γ。然而，细胞毒性功能对这种保护作用的贡献尚未得到研究。我们研究了过敏原特异性 CTL 的细胞毒性功能对过敏性气道炎症的治疗作用的贡献。我们使用了一种过敏性气道炎症的小鼠模型，其中小鼠通过鼻腔途径对 OVA 进行致敏，然后用相同的 Ag 进行挑战。通过用树突状细胞（DC）免疫或通过过继转移体外激活的 CD8(+)T 细胞，在这些小鼠中引发 CTL。评估了过敏性哮喘的标志性特征，如支气管肺泡灌洗液和黏液中嗜酸性粒细胞的浸润。过敏原特异性 CTL 对过敏性气道炎症的抑制作用严重依赖于穿孔素的表达，穿孔素是细胞毒性机制的关键组成部分。从过敏原致敏小鼠的肺部回收了具有足够穿孔素和缺乏穿孔素的过敏原特异性 CTL，并在上皮内过敏原挑战时上调 CD69 表达并分泌细胞因子 IFN-γ和 TNF-α。然而，只有具有足够穿孔素的 CTL 抑制气道中的嗜酸性粒细胞浸润、黏液产生和细胞因子在支气管肺泡灌洗液中的积累。用过敏原特异性 CTL 治疗，但不是它们的缺乏穿孔素的对应物，也与纵隔淋巴结中 DC 数量的减少有关。我们的数据表明，过敏原特异性 CD8(+)T 细胞的细胞毒性功能对于其调节过敏性气道炎症的能力至关重要。
