Proteasome activity regulates CD8+ T lymphocyte metabolism and fate specification

Christella E. Widjaja, Jocelyn G. Olvera, Patrick J. Metz, Anthony T. Phan, Jeffrey N. Savas, Gerjan De Bruin, Yves Leestemaker, Celia R. Berkers, Annemieke De Jong, Bogdan I. Florea, Kathleen Fisch, Justine Lopez, Stephanie H. Kim, Daniel A. Garcia, Stephen Searles, Jack D. Bui, Aaron N. Chang, John R. Yates, Ananda W. Goldrath, Hermen S. OverkleeftHuib Ovaa, John T. Chang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

During an immune response, CD8+ T lymphocytes can undergo asymmetric division, giving rise to daughter cells that exhibit distinct tendencies to adopt terminal effector and memory cell fates. Here we show that "pre-effector" and "pre-memory" cells resulting from the first CD8+ T cell division in vivo exhibited low and high rates of endogenous proteasome activity, respectively. Pharmacologic reduction of proteasome activity in CD8+ T cells early during differentiation resulted in acquisition of terminal effector cell characteristics, whereas enhancement of proteasome activity conferred attributes of memory lymphocytes. Transcriptomic and proteomic analyses revealed that modulating proteasome activity in CD8+ T cells affected cellular metabolism. These metabolic changes were mediated, in part, through differential expression of Myc, a transcription factor that controls glycolysis and metabolic reprogramming. Taken together, these results demonstrate that proteasome activity is an important regulator of CD8+ T cell fate and raise the possibility that increasing proteasome activity may be a useful therapeutic strategy to enhance the generation of memory lymphocytes.

Original languageEnglish (US)
Pages (from-to)3609-3623
Number of pages15
JournalJournal of Clinical Investigation
Volume127
Issue number10
DOIs
StatePublished - Oct 2 2017

ASJC Scopus subject areas

  • Medicine(all)

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