Slfn2 mutation-induced loss of T-cell quiescence leads to elevated de novo sterol synthesis

Ibrahim Omar, Oren Rom, Michael Aviram, Leonor Cohen-Daniel, Abraham K. Gebre, John S. Parks, Michael Berger*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Acquisition of a ‘quiescence programme’ by naive T cells is important to provide a stress-free environment and resistance to apoptosis while preserving their responsiveness to activating stimuli. Therefore, the survival and proper function of naive T cells depends on their ability to maintain quiescence. Recently we demonstrated that by preventing chronic unresolved endoplasmic reticulum (ER) stress, Schlafen2 (Slfn2) maintains a stress-free environment to conserve a pool of naive T cells ready to respond to a microbial invasion. These findings strongly suggest an intimate association between quiescence and stress signalling. However, the connection between ER stress conditions and loss of T-cell quiescence is unknown. Here we demonstrate that homeostasis of cholesterol and lipids, is disrupted in T cells and monocytes from Slfn2-mutant, elektra, mice with higher levels of lipid rafts and lipid droplets found in these cells. Moreover, elektra T cells had elevated levels of free cholesterol and cholesteryl ester due to increased de novo synthesis and higher levels of the enzyme HMG-CoA reductase. As cholesterol plays an important role in the transition of T cells from resting to active state, and ER regulates cholesterol and lipid synthesis, we suggest that regulation of cholesterol levels through the prevention of ER stress is an essential component of the mechanism by which Slfn2 regulates quiescence.

Original languageAmerican English
Pages (from-to)484-493
Number of pages10
JournalImmunology
Volume152
Issue number3
DOIs
StatePublished - Nov 2017

Bibliographical note

Publisher Copyright:
© 2017 John Wiley & Sons Ltd

Keywords

  • Slfn2
  • T cell quiescence
  • cholesterol synthesis

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