Chaperone-mediated autophagy (CMA) is a selective form of autophagy that contributes to the maintenance of cellular homeostasis. CMA activity declines with age in most tissues and systems, including the immune system, due to a reduction in levels of lysosome-associated membrane protein type 2A (LAMP2A), an essential CMA component. In this study, we show that overexpressing a copy of hLAMP2A within T cells since middle-age can prevent some of their age-associated loss of function. Our data support the idea that preserving LAMP2A expression with age through genetic means leads to enhanced proliferative responses, decreased number of regulatory T cell populations, and down-regulated expression of inhibitory receptors by T cells. During aging, elevated numbers of these immunosuppressive T cell populations significantly contribute to the age-associated downregulation of T cell responses. Using comparative proteomics, we confirm that preservation of CMA activity in old mice prevents age-related changes in both the resting and the activated T cell proteome. We also explore the effect of using first-in-class small molecule activators of CMA and demonstrate improved T cell response upon their administration to old mice. We conclude that sustaining CMA activity constitutes a potentially viable therapeutic approach to improving T cell function with age.

中文翻译：

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老年小鼠 LAMP2A 表达的恢复导致 T 细胞区室发生变化，从而支持免疫功能的改善


伴侣介导的自噬 （CMA） 是一种选择性形式的自噬，有助于维持细胞稳态。由于溶酶体相关膜蛋白 2A 型 （LAMP2A） 水平降低，大多数组织和系统（包括免疫系统）的 CMA 活性会随着年龄的增长而下降，这是 CMA 的重要组成部分。在这项研究中，我们表明，自中年以来在 T 细胞中过表达 hLAMP2A 的拷贝可以防止它们与年龄相关的一些功能丧失。我们的数据支持这样一种观点，即通过遗传手段随年龄增长保持 LAMP2A 表达会导致增殖反应增强、调节性 T 细胞群数量减少以及 T 细胞抑制性受体表达下调。在衰老过程中，这些免疫抑制性 T 细胞群数量的增加显着导致与年龄相关的 T 细胞反应下调。使用比较蛋白质组学，我们证实在老年小鼠中保持 CMA 活性可以防止静息和活化的 T 细胞蛋白质组发生与年龄相关的变化。我们还探讨了使用 CMA 的一流小分子激活剂的效果，并证明了它们在老年小鼠给药后 T 细胞反应得到改善。我们得出结论，维持 CMA 活性构成了随着年龄增长而改善 T 细胞功能的潜在可行治疗方法。