Sustained mTORC1 activation in activated T cells impairs vaccine responses in older individuals
Xiaorong Lin, Yanhua Du, Shuo Kan, Junjie Chen, Junjie Chen, Yunxue Yin, Linlin Li, Jingwen Chen, Jingwen Chen, Wuhua Jiang, Wenqiang Cao, Chulwoo Kim, Liang Chen, Shiwen Wang, Jörg J. Goronzy, Jun Jin
Abstract
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.