Lin Xiaorong, Du Yanhua, Kan Shuo, Chen Junjie, Yin Yunxue, Li Linlin, Chen Jingwen, Jiang Wenrong, Cao Wenqiang, Kim Chulwoo, Chen Liang, Wang Shiwen, Goronzy Jorg J, Jin Jun
Multiscale Research Institute for Complex Systems, Fudan University, Shanghai, China.
Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
Sci Adv. 2025 Apr 18;11(16):eadt4881. doi: 10.1126/sciadv.adt4881.
T cell aging contributes to the lower vaccine efficacy in older adults, yet the molecular mechanism remains elusive. Here, we show the density of initially responding naïve CD4 T cells is instructive in T follicular helper (TFH) cell fate decisions and declines with age. A lower number of initially responding cells did not affect TFH differentiation at peak responses after immunization but accounted for an increased contraction phase manifesting as a larger loss of CXCR5 expression. Mechanistically, cells activated at a lower initial density had more sustained mammalian target of rapamycin complex 1 (mTORC1) activities that impair CXCR5 maintenance. YAP-dependent regulation of SLC7A5 involved in the cell density-dependent regulation of mTORC1 activities and TFH loss. Old mice fed with a leucine-restricted diet after peak responses showed smaller TFH loss and improved humoral immune responses. Attenuating mTORC1 signaling after peak response is a strategy to boost vaccine responses in older individuals.
T细胞衰老导致老年人疫苗效力降低，但其分子机制仍不清楚。在此，我们表明初始应答的幼稚CD4 T细胞密度对滤泡辅助性T（TFH）细胞的命运决定具有指导作用，且随年龄增长而下降。较低数量的初始应答细胞在免疫后的峰值反应中不影响TFH分化，但在收缩期占比增加，表现为CXCR5表达的更大损失。机制上，以较低初始密度激活的细胞具有更持续的雷帕霉素复合物1（mTORC1）活性，这会损害CXCR5的维持。YAP依赖的SLC7A5调节参与了mTORC1活性和TFH损失的细胞密度依赖性调节。在峰值反应后喂食亮氨酸限制饮食的老年小鼠显示出较小的TFH损失和改善的体液免疫反应。在峰值反应后减弱mTORC1信号是增强老年个体疫苗反应的一种策略。
