Autophagy is a critical regulator of memory CD8(+) T cell formation.
Autophagy is a critical regulator of memory CD8(+) T cell formation.
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DOI：
10.7554/elife.03706
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发表时间：
2014-11-11
期刊：
影响因子：
7.7
通讯作者：
Simon AK
中科院分区：
文献类型：
--
作者：
Puleston DJ;Zhang H;Powell TJ;Lipina E;Sims S;Panse I;Watson AS;Cerundolo V;Townsend AR;Klenerman P;Simon AK
在感染期间，CD8+T细胞最初会膨胀，然后收缩，留下一个小的记忆池，提供持久的免疫力。虽然已经描述了CD8+T细胞的记忆形成在老年时会出现缺陷，但其细胞机制在很大程度上还不清楚。自噬是大量物质的主要细胞溶酶体降解途径，已知其水平随着年龄的增长而下降。在这项研究中，我们描述了自噬在CD8+T细胞记忆形成中的一个新角色。在T细胞中缺乏自噬基因ATG7的小鼠无法建立CD8+T细胞对流感和MCMV感染的记忆。有趣的是，老年小鼠的CD8+T细胞的自噬水平降低了。我们可以使用复合亚精胺以自噬依赖的方式恢复老年小鼠的CD8+T细胞反应。这项研究揭示了老年人CD8+T细胞记忆不良的细胞内在解释，并可能提供新的免疫调节剂来提高老年人的免疫力。Http://dx.doi.org/10.7554/eLife.03706.001在面对感染时，免疫系统通过产生许多被称为CD8+T细胞的杀手免疫细胞来进行攻击性反应，这些细胞识别并摧毁任何感染了入侵病原体的细胞。产生的杀伤细胞的数量取决于感染的程度。一旦感染得到控制，大多数CD8+T细胞就会死亡。保留下来的少量记忆细胞--记忆细胞--“记住”病原体，这样，如果病原体再次入侵人体，它们可以帮助免疫系统更快、更有效地做出反应。记忆细胞对疫苗的有效性也至关重要，其中许多疫苗会将死亡或减弱的病原体引入体内。这不会导致感染，但确实允许免疫系统创造记忆细胞，这些细胞能够在未来抵御相同的病原体。然而，疫苗只对能够产生和维持记忆细胞的个人有效，而许多老年人不太能做到这一点。维持细胞的一个重要系统称为自噬，它会破坏和清除所有细胞随着时间的推移而积累的“垃圾”和有毒副产物。如果没有自噬，细胞产生能量的能力就会降低，可能会死亡。Puleston等人。表明自噬在老年小鼠中开始失败，这阻止了正确的记忆反应的形成。此外，缺乏自噬所需的重要基因的小鼠在感染流感等病毒后无法产生记忆细胞。Puleston等人。研究发现，使用一种名为亚精胺的化学物质促进老年小鼠的自噬，有助于恢复小鼠创造和维持记忆细胞的能力。亚精胺也存在于许多组织中。与其他年龄相仿的小鼠相比，注射亚精胺的小鼠在接种疫苗后对流感的免疫力更强。为了更好地了解亚精胺是如何发挥作用的，还需要进一步的研究，看看它是否可以开发成一种安全地增强人类免疫系统的药物。DOI：http://dx.doi.org/10.7554/eLife.03706.002
During infection, CD8+ T cells initially expand then contract, leaving a small memory pool providing long lasting immunity. While it has been described that CD8+ T cell memory formation becomes defective in old age, the cellular mechanism is largely unknown. Autophagy is a major cellular lysosomal degradation pathway of bulk material, and levels are known to fall with age. In this study, we describe a novel role for autophagy in CD8+ T cell memory formation. Mice lacking the autophagy gene Atg7 in T cells failed to establish CD8+ T cell memory to influenza and MCMV infection. Interestingly, autophagy levels were diminished in CD8+ T cells from aged mice. We could rejuvenate CD8+ T cell responses in elderly mice in an autophagy dependent manner using the compound spermidine. This study reveals a cell intrinsic explanation for poor CD8+ T cell memory in the elderly and potentially offers novel immune modulators to improve aged immunity. DOI: http://dx.doi.org/10.7554/eLife.03706.001 In the face of an infection, the immune system mounts an aggressive response by producing many copies of killer immune cells called CD8+ T cells that recognize and destroy any cells infected with the invading pathogen. The number of killer cells produced depends on the extent of the infection. Once the infection has been brought under control, most of the CD8+ T cells die off. The small numbers that are retained—called memory cells—‘remember’ the pathogen, so that if it invades the body again, they can help the immune system to respond more quickly and effectively. Memory cells are also critical to the effectiveness of vaccines, many of which introduce a dead or weakened pathogen into the body. This does not cause an infection, but does allow the immune system to create memory cells that are able to fend off the same pathogen in the future. However, vaccines only work in individuals that are able to produce and maintain memory cells, which many older people are less able to do. An important system that maintains cells, called autophagy, destroys and removes the ‘junk’ and toxic by products that all cells accumulate over time as a result of normal cell functions. Without autophagy, cells become less able to produce energy and they may die. Puleston et al. show that autophagy begins to fail in old mice, which prevents the formation of a proper memory response. In addition, mice that lack an important gene needed for autophagy are unable to produce memory cells after being infected with viruses such as influenza. Puleston et al. found that boosting autophagy in older mice using a chemical called spermidine—which is also found naturally in many tissues—helped to restore the mice's ability to create and maintain memory cells. Spermidine-treated mice developed a stronger immunity to influenza after vaccination compared with other mice of a similar age. Further research is required to better understand how spermidine works to see if it could be developed into a drug that safely boosts the immune system of humans. DOI: http://dx.doi.org/10.7554/eLife.03706.002