Impact of sex steroid ablation on viral, tumour and vaccine responses in aged mice.
Impact of sex steroid ablation on viral, tumour and vaccine responses in aged mice.
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DOI：
10.1371/journal.pone.0042677
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Boyd RL
中科院分区：
文献类型：
--
作者：
Heng TS;Reiseger JJ;Fletcher AL;Leggatt GR;White OJ;Vlahos K;Frazer IH;Turner SJ;Boyd RL
最近的证据表明，随着年龄的增长，对病毒感染的抵抗力下降主要是由于naïve抗原特异性T细胞的逐渐丧失。因此，将naïve T细胞库恢复到年轻健康成人的水平可能会提高老年人对感染的防御能力。我们之前已经表明，性类固醇消融（SSA）可以使老化的胸腺恢复活力，并增加naïve T细胞的胸腺输出，但目前尚不清楚T细胞的反应是否得到改善。使用临床相关疾病的小鼠模型，我们现在证明SSA增加了naïve T细胞对抗原的反应数量，从而增强了老年小鼠的效应反应。具体来说，老年小鼠表现出清除甲型流感病毒的延迟，这与特异性细胞毒性活性降低有关。这是由于反应幅度降低，而不是效应T细胞功能的内在缺陷。在SSA后，老年小鼠表现出增加的T细胞反应性，恢复有效的病毒清除。我们进一步证明，SSA降低了老年小鼠诱导肿瘤的发生率，并可能增加它们对低剂量人乳头瘤病毒疫苗清除预先形成的肿瘤的反应性。由于胸腺切除术消除了SSA后T细胞数量和反应性的增加，我们提出SSA对T细胞的影响依赖于胸腺再激活和随后外周T细胞池中新迁移naïve T细胞的补充。这些发现对改善老年人预防感染和免疫应答的策略具有重要意义。
Recent evidence suggests that the decline in resistance to viral infections with age occurs predominantly as a result of a gradual loss of naïve antigen-specific T cells. As such, restoration of the naïve T cell repertoire to levels seen in young healthy adults may improve defence against infection in the aged. We have previously shown that sex steroid ablation (SSA) rejuvenates the ageing thymus and increases thymic export of naïve T cells, but it remains unclear whether T cell responses are improved. Using mouse models of clinically relevant diseases, we now demonstrate that SSA increases the number of naïve T cells able to respond to antigen, thereby enhancing effector responses in aged mice. Specifically, aged mice exhibit a delay in clearing influenza A virus, which correlates with diminished specific cytotoxic activity. This is due to a decreased magnitude of response and not an intrinsic defect in effector T cell function. Upon SSA, aged mice exhibit increased T cell responsiveness that restores efficient viral clearance. We further demonstrate that SSA decreases the incidence of an inducible tumour in aged mice and can potentially increase their responsiveness to a low-dose human papillomavirus vaccine in clearing pre-formed tumours. As thymectomy abrogates the increase in T cell numbers and responsiveness following SSA, we propose that the T cell effects of SSA are dependent on thymic reactivation and subsequent replenishment of the peripheral T cell pool with newly emigrated naïve T cells. These findings have important implications for strategies to improve protection from infection and responsiveness to vaccination in the aged.
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DOI：
10.1098/rspb.1974.0056
发表时间：
1974-01-01
期刊：
PROCEEDINGS OF THE ROYAL SOCIETY SERIES B-BIOLOGICAL SCIENCES
影响因子：
--
作者：
CASTRO, JE
通讯作者：
CASTRO, JE
影响因子：
5.5
作者：
McElhaney, JE;Hooton, JW;Bleackley, RC
通讯作者：
Bleackley, RC
影响因子：
5
作者：
Hannoun, C;Megas, F;Piercy, J
通讯作者：
Piercy, J
影响因子：
4.4
作者：
Dudakov, Jarrod A.;Goldberg, Gabrielle L.;Boyd, Richard L.
通讯作者：
Boyd, Richard L.
影响因子：
5.3
作者：
Po, JLZ;Gardner, EM;Murasko, DM
通讯作者：
Murasko, DM