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J Clin Invest. 2017 Oct 2;127(10):3609-3623. doi: 10.1172/JCI90895. Epub 2017 Aug 28.

Proteasome activity regulates CD8+ T lymphocyte metabolism and fate specification.

Author information

1
Department of Medicine and.
2
Division of Biological Sciences, UCSD, La Jolla, California, USA.
3
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.
4
Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
5
Division of Cell Biology II, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
6
Department of Chemical Immunology, Leiden University Medical Center, Leiden, The Netherlands.
7
Biomolecular Mass Spectrometry and Proteomics, Utrecht University, Utrecht, The Netherlands.
8
Center for Computational Biology and Bioinformatics, Department of Medicine, and.
9
Department of Pathology, UCSD, La Jolla, California, USA.

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.

PMID:
28846070
PMCID:
PMC5617668
DOI:
10.1172/JCI90895
[Indexed for MEDLINE]
Free PMC Article

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