A Major Role for Bim in Regulatory T Cell Homeostasis
A Major Role for Bim in Regulatory T Cell Homeostasis
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DOI：
10.4049/jimmunol.1001505
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发表时间：
2011-01-01
影响因子：
4.4
通讯作者：
Hildeman, David A.
中科院分区：
文献类型：
--
作者：
Chougnet, Claire A.;Tripathi, Pulak;Hildeman, David A.
我们以前已经表明，调节性T细胞（Treg）在老年动物中显著积累，并对控制持续感染的能力产生负面影响。然而，Treg的年龄依赖性累积的机制仍不清楚。在这项研究中，我们发现Treg随着年龄的增长而积累是进行性的，可能不是胸腺输出增加，外周增殖增加或外周转化增强的结果。相反，我们发现来自老年小鼠的Treg比来自年轻小鼠的Treg更能抵抗细胞凋亡。尽管来自老年小鼠的Treg具有增加的功能性IL-7 R α的表达，但我们发现IL-7 R信号传导对于Treg在体内的维持不是必需的。值得注意的是，与来自年轻小鼠的Treg相比，老年Treg表现出促凋亡分子Bim的表达降低。此外，在没有Bim的情况下，Treg迅速积累，到6个月龄时占CD 4（+）T细胞区室的>25%。此外，Treg在Bim缺陷小鼠中的积累发生在细胞离开过渡性近期胸腺移出区室之后。从机制上讲，我们表明IL-2驱动Bim（lo）Treg的优先增殖和积累。总的来说，我们的数据表明，IL-2的慢性刺激导致具有低Bim表达的Treg的优先扩增，这有利于它们在老年宿主中的存活和积累。免疫学杂志，2011，186：156-163。
We have previously shown that regulatory T cells (Treg) accumulate dramatically in aged animals and negatively impact the ability to control persistent infection. However, the mechanisms underlying the age-dependent accrual of Treg remain unclear. In this study, we show that Treg accumulation with age is progressive and likely not the result of increased thymic output, increased peripheral proliferation, or from enhanced peripheral conversion. Instead, we found that Treg from aged mice are more resistant to apoptosis than Treg from young mice. Although Treg from aged mice had increased expression of functional IL-7R alpha, we found that IL-7R signaling was not required for maintenance of Treg in vivo. Notably, aged Treg exhibit decreased expression of the proapoptotic molecule Bim compared with Treg from young mice. Furthermore, in the absence of Bim, Treg accumulate rapidly, accounting for >25% of the CD4(+) T cell compartment by 6 mo of age. Additionally, accumulation of Treg in Bim-deficient mice occurred after the cells left the transitional recent thymic emigrant compartment. Mechanistically, we show that IL-2 drives preferential proliferation and accumulation of Bim(lo) Treg. Collectively, our data suggest that chronic stimulation by IL-2 leads to preferential expansion of Treg having low expression of Bim, which favors their survival and accumulation in aged hosts. The Journal of Immunology, 2011, 186: 156-163.