FOXO1 deficiency impairs proteostasis in aged T cells

Jun Jin, Xuanying Li, Bin Hu, Chulwoo Kim, Wenqiang Cao, Huimin Zhang, Cornelia M. Weyand, Jorg J. Goronzy

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)


T cell differentiation involves the dynamic regulation of FOXO1 expression, which rapidly declines after activation and is subsequently restored. Reexpression is impaired in naïve CD4+ T cell responses from older individuals. Here, we show that FOXO1 promotes lysosome function through the induction of the key transcription factor for lysosomal proteins, TFEB. Subdued FOXO1 reexpression in activated CD4+ T cells impairs lysosomal activity, causing an expansion of multivesicular bodies (MVBs). Expansion of the MVB compartment induces the sequestration of glycogen synthase kinase 3β (GSK3β), thereby suppressing protein turnover and enhancing glycolytic activity. As a consequence, older activated CD4+ T cells develop features reminiscent of senescent cells. They acquire an increased cell mass, preferentially differentiate into short-lived effector T cells, and secrete exosomes that harm cells in the local environment through the release of granzyme B.

Original languageEnglish
Article numberaba1808
JournalScience Advances
Issue number17
Publication statusPublished - 2020 Apr
Externally publishedYes

Bibliographical note

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© 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

ASJC Scopus subject areas

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