Naïve CD8+ t-cells engage a versatile metabolic program upon activation in humans and differ energetically from memory CD8+ T-cells

Francesco Nicoli, Laura Papagno, Justin J. Frere, Mariela Pires Cabral-Piccin, Emmanuel Clave, Emma Gostick, Antoine Toubert, David A. Price, Antonella Caputo, Victor Appay

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Background: Characterization of the intracellular biochemical processes that regulate the generation and maintenance of effector and memory CD8+ T-cells from naïve precursors is essential for our understanding of adaptive immune responses and the development of immunotherapies. However, the metabolic determinants of antigen-driven activation and differentiation remain poorly defined, especially in humans. Methods: We used a variety of different approaches, including gene expression profiling and measurements of nutrient flux, to characterize the basal and activation-induced energetic requirements of naïve and phenotypically-defined subsets of human memory CD8+ T-cells. Findings: Profound metabolic differences were apparent as a function of differentiation status, both at rest and in response to stimulation via the T cell receptor (TCR). Of particular note, resting naïve CD8+ T cells were largely quiescent, but rapidly upregulated diverse energetic pathways after ligation of surface-expressed TCRs. Moreover, autophagy and the mechanistic target of rapamycin (mTOR)-dependent glycolytic pathway were identified as critical mediators of antigen-driven priming in the naïve CD8+ T cell pool, the efficiency of which was dampened by the presence of neutral lipids and fatty acids. Interpretation: These observations provide a metabolic roadmap of the CD8+ T-cell compartment in humans and reveal potentially selective targets for novel immunotherapies.

Original languageEnglish
Article number2736
Pages (from-to)1-12
Number of pages12
JournalFrontiers in Immunology
Volume9
DOIs
StatePublished - Dec 2018
Externally publishedYes

Keywords

  • CD8 T-lymphocytes
  • Immunometabolism
  • MTOR
  • Naïve T-cells
  • Priming

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