Restoration of LAMP2A expression in old mice leads to changes in the T cell compartment that support improved immune function

• 成果类型: Article
• 署名作者: Reynolds, Cara A.; Pelka, Sandra; Gjergjova, Floralba; Tasset, Inmaculada; Khawaja, Rabia R.; Lindenau, Kristen; Krause, Gregory J.; Gavathiotis, Evripidis; Cuervo, Ana Maria; Macian, Fernando; Heissmeyer, Vigo
• 署名单位: Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University; Universidad de Cordoba; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14149
• DOI: 10.1073/pnas.2322929121
• 发表日期: 2024-09-17
• 关键词: chaperone-mediated autophagy; AGE; receptor; immunosenescence; accumulation; proteostasis; inflammation; degradation; proteins; decline

摘要

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.