Dahlquist Korbyn J V, Dehm Emma M, Smith Declan M, Lucas Erin D, Pierson Mark, Hamilton Sara E, Camell Christina D
Biochemistry, Molecular Biology, and Biophysics Graduate Program, Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA.
Masonic Institute On the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA.
Geroscience. 2025 Jun 6. doi: 10.1007/s11357-025-01723-5.
CD8 T cells exhibit distinct changes with aging, including a diminished naïve cell pool, an expansion of memory and exhausted cells, and altered effector molecule production, altogether leading to increased susceptibility to infection. They have reduced cytotoxicity in vivo, but increased granule content and faster cytotoxic kinetics to target cells in vitro. Whether CD8 T cells from old mice degranulate when activated in vivo, within the aged environment, is unknown. This study investigates in vitro and in vivo degranulation of CD8 T cells from young and old mice during supraphysiological aCD3 stimulation and two types of infection. Actively degranulating CD8 CD44 T cells were identified by positive labeling after a two-hour exposure to granule-specific fluorescent antibodies (CD107a and CD107b). Surprisingly, CD8 T cells from old mice challenged with supraphysiological TCR-specific stimulation exhibited higher levels of degranulation as compared to their young counterparts. This effect is more prominent in vitro and can be partially explained by the age-specific increase in CD8 CD44 CD62L cells. However, during microbial exposure or LCMV Armstrong infection, we show that CD8 CD44 and antigen-specific T cells from old mice have reduced degranulation, consistent with the diminished cytotoxic capacity. These data highlight the preserved intrinsic cytotoxic capacity of memory CD8 T cells from old mice and suggest that the aged microenvironment and type of stimulation are contributing factors to the lower degranulation and cytotoxic capacity of these cells. This provides insight into the potential of increasing T cell activation to improve vaccine approaches in the elderly.
CD8 T细胞随着衰老呈现出明显变化，包括初始细胞池减少、记忆细胞和耗竭细胞扩增以及效应分子产生改变，这些变化共同导致对感染的易感性增加。它们在体内的细胞毒性降低，但在体外颗粒含量增加且对靶细胞的细胞毒性动力学更快。老年小鼠的CD8 T细胞在衰老环境中于体内被激活时是否会脱颗粒尚不清楚。本研究调查了年轻和老年小鼠的CD8 T细胞在超生理aCD3刺激和两种感染过程中的体外和体内脱颗粒情况。在暴露于颗粒特异性荧光抗体（CD107a和CD107b）两小时后，通过阳性标记鉴定出正在积极脱颗粒的CD8 CD44 T细胞。令人惊讶的是，与年轻小鼠的CD8 T细胞相比，受到超生理TCR特异性刺激的老年小鼠的CD8 T细胞表现出更高水平的脱颗粒。这种效应在体外更为显著，并且可以部分由CD8 CD44 CD62L细胞随年龄增长的增加来解释。然而，在微生物暴露或淋巴细胞脉络丛脑膜炎病毒（LCMV）阿姆斯特朗株感染期间，我们发现老年小鼠的CD8 CD44和抗原特异性T细胞脱颗粒减少，这与细胞毒性能力降低一致。这些数据突出了老年小鼠记忆CD8 T细胞保留的内在细胞毒性能力，并表明衰老的微环境和刺激类型是导致这些细胞脱颗粒和细胞毒性能力降低的因素。这为提高T细胞激活以改善老年人疫苗接种方法的潜力提供了见解。
