The Development of Airway Hyperreactivity in T-bet-Deficient Mice Requires CD1d-Restricted NKT Cells
The Development of Airway Hyperreactivity in T-bet-Deficient Mice Requires CD1d-Restricted NKT Cells
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DOI：
10.4049/jimmunol.0803339
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发表时间：
2009-03-01
影响因子：
4.4
通讯作者：
Umetsu, Dale T.
中科院分区：
文献类型：
--
作者：
Kim, Hye Young;Pichavant, Muriel;Umetsu, Dale T.
由于终末成熟的停止，T-bet（-/-）小鼠在外周产生不变NKT（iNKT）细胞的能力方面存在严重缺陷，但尽管存在这种缺陷，T-bet（-/-）小鼠仍会发生自发性气道高反应性（AHR）和气道炎症。因为在某些情况下，AHR的发生需要iNKT细胞的存在，我们试图通过在几种不同的哮喘小鼠模型中检查T-bet（-/-）小鼠，包括自发的、OVA诱导的和α-半乳糖神经酰胺（α-GalCer）诱导的AHR，更清楚地了解T-bet（-/-）小鼠中AHR是如何发生的。令人惊讶的是，我们发现施用非常特异性地激活iNKT细胞的α-GalCer大大增加了T-bet（-/-）小鼠中的AHR应答。此外，在T-bet（-/-）小鼠中，自发AHR以及用OVA或α-GalCer诱导的AHR均通过使用抗CD 1d阻断mAb阻断CD 1d（iNKT细胞的限制元件）消除。尽管与野生型小鼠相比，T-bet（-/-）小鼠中iNKT细胞的数量减少，但剩余的iNKT细胞主要产生IL-4和IL-13，并且仅产生极少量的IFN-γ。因此，我们得出结论，在T-bet（-/-）小鼠中发展的AHR依赖于iNKT细胞的存在，而T-bet（-/-）具有减少的iNKT细胞数量，这些对于AHR的发展是足够的。免疫学杂志，2009，182：3252-3261.
T-bet(-/-) mice have been shown to have a profound deficiency in the ability to generate invariant NKT (iNKT) cells in the periphery due to a halt in terminal maturation, but despite this deficiency, T-bet(-/-) mice develop spontaneous airway hyperreactivity (AHR) and airway inflammation. Because in some situations the development of AHR requires the presence of iNKT cells, we sought to more clearly understand how AHR develops in T-bet(-/-) mice by examining T-bet(-/-) mice in several distinct mouse models of asthma, including spontaneous, OVA-induced and alpha-galactosylceramide (alpha-GalCer)-induced AHR. Surprisingly, we found that administration of a-GalCer, which very specifically activates iNKT cells, greatly increased the AHR response in the T-bet(-/-) mice. Moreover, in T-bet(-/-) mice, spontaneous AHR as well as AHR induced with OVA or alpha-GalCer were all eliminated by blocking CD1d, the restricting element of iNKT cells, using an anti-CD1d-blocking mAb. Although the number of the iNKT cells in T-bet(-/-) mice was reduced compared with that in wild-type mice, the remaining iNKT cells produced primarily IL-4 and IL-13, and only minimal amounts of IFN-gamma. We conclude therefore that the AHR that develops in T-bet(-/-) mice is dependent on the presence of iNKT cells, and that whereas T-bet(-/-) have reduced numbers of iNKT cells, these are sufficient for the development of AHR. The Journal of Immunology, 2009, 182: 3252-3261.