Mitochondrial Priming by CD28

Ramon I. Klein Geltink, David O'Sullivan, Mauro Corrado, Anna Bremser, Michael D. Buck, Joerg M. Buescher, Elke Firat, Xuekai Zhu, Gabriele Niedermann, George Caputa, Beth Kelly, Ursula Warthorst, Anne Rensing-Ehl, Ryan L. Kyle, Lana Vandersarren, Jonathan D. Curtis, Annette E. Patterson, Simon Lawless, Katarzyna Grzes, Jing QiuDavid E. Sanin, Oliver Kretz, Tobias B. Huber, Sophie Janssens, Bart N. Lambrecht, Angelika S. Rambold, Edward J. Pearce, Erika L. Pearce

Research output: Contribution to journalArticlepeer-review

Abstract

T cell receptor (TCR) signaling without CD28 can elicit primary effector T cells, but memory T cells generated during this process are anergic, failing to respond to secondary antigen exposure. We show that, upon T cell activation, CD28 transiently promotes expression of carnitine palmitoyltransferase 1a (Cpt1a), an enzyme that facilitates mitochondrial fatty acid oxidation (FAO), before the first cell division, coinciding with mitochondrial elongation and enhanced spare respiratory capacity (SRC). microRNA-33 (miR33), a target of thioredoxin-interacting protein (TXNIP), attenuates Cpt1a expression in the absence of CD28, resulting in cells that thereafter are metabolically compromised during reactivation or periods of increased bioenergetic demand. Early CD28-dependent mitochondrial engagement is needed for T cells to remodel cristae, develop SRC, and rapidly produce cytokines upon restimulation—cardinal features of protective memory T cells. Our data show that initial CD28 signals during T cell activation prime mitochondria with latent metabolic capacity that is essential for future T cell responses. Costimulatory signals during the initial phase of T cell activation prime mitochondria with latent metabolic capacity essential for future T cell responses.

Original languageEnglish (US)
Pages (from-to)385-397.e11
JournalCell
Volume171
Issue number2
DOIs
StatePublished - Oct 5 2017
Externally publishedYes

Keywords

  • CD28
  • CD8 T cells
  • Cpt1a
  • adoptive cellular immunotherapy
  • costimulation
  • memory T cells
  • mir33
  • mitochondrial cristae remodeling
  • mitochondrial morphology
  • spare respiratory capacity

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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