ICOS/ICOSL interaction is required for CD4+ invariant NKT cell function and homeostatic survival
ICOS/ICOSL interaction is required for CD4+ invariant NKT cell function and homeostatic survival
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DOI：
10.4049/jimmunol.180.8.5448
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发表时间：
2008-04-15
影响因子：
4.4
通讯作者：
DeKruyff, Rosemarie H.
中科院分区：
文献类型：
--
作者：
Akbari, Omid;Stock, Philippe;DeKruyff, Rosemarie H.
气道高反应性（AHR）是哮喘的一个主要特征，其发生需要不变NKT（iNKT）细胞的存在。在哮喘小鼠模型中，我们证明了AHR的诱导需要iNKT细胞的ICOS共刺激。ICOS在初始和活化的iNKT细胞上均高度表达，并且ICOS在CD 4（+）iNKT细胞上的表达高于在CD 4（-）iNKT细胞上的表达。此外，在ICOS-/-和ICOSL-/-小鼠的脾脏和肝脏中，CD 4（+）iNKT细胞的数量显著较低，并且ICOS-/-小鼠中剩余的iNKT细胞功能失调，当过继转移到iNKT细胞缺陷型J α 18（-/-）小鼠中时，不能重建AHR。此外，用α-GalCer直接活化iNKT细胞在野生型小鼠中诱导AHR，但在ICOS-/-小鼠中未能诱导AHR。ICOS-/- iNKT细胞诱导AHR的失败部分是由于ICOS-/- iNKT细胞在活化时不能产生IL-4和IL-13。此外，由于诱导细胞凋亡，转移到ICOSL-/-小鼠中的野生型iNKT细胞的存活率大大降低。这些结果表明，ICOS共刺激在iNKT细胞诱导AHR中起主要作用，并且是CD 4（+）iNKT细胞功能、稳态和外周存活所必需的。
The development of airway hyperreactivity (AHR), a cardinal feature of asthma, requires the presence of invariant NKT (iNKT) cells. In a mouse model of asthma, we demonstrated that the induction of AHR required ICOS costimulation of iNKT cells. ICOS was highly expressed on both naive and activated iNKT cells, and expression of ICOS was greater on the CD4(+) iNKT than on CD4(-) iNKT cells. Furthermore, the number of CD4(+) iNKT cells was significantly lower in spleens and livers of ICOS-/- and ICOSL-/- mice, and the remaining iNKT cells in ICOS-/- mice were dysfunctional and failed to reconstitute AHR when adoptively transferred into iNKT cell-deficient J alpha 18(-/-) mice. In addition, direct activation of iNKT cells with alpha-GalCer, which induced AHR in wild-type mice, failed to induce AHR in ICOS-/- mice. The failure of ICOS-/- iNKT cells to induce AHR was due in part to an inability of the ICOS-/- iNKT cells to produce IL-4 and IL-13 on activation. Moreover, survival of wild-type iNKT cells transferred into ICOSL-/- mice was greatly reduced due to the induction of apoptosis. These results indicate that ICOS costimulation plays a major role in induction of AHR by iNKT cells and is required for CD4(+) iNKT cell function, homeostasis, and survival in the periphery.