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.
Bibliographical noteFunding Information:
This work was supported by the NIH (R01 AR042527, R01 HL117913, R01 AI108906, R01 HL142068, and P01 HL129941 to C.M.W. and R01 AI108891, R01 AG045779, U19 AI057266, and R01 AI129191 to J.J.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
© 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).
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