Nicoli, Francesco, Papagno, Laura, Frere, Justin J., Cabral-Piccin, Mariela Pires, Clave, Emmanuel, Gostick, Emma, Toubert, Antoine, Price, David A.  ORCID: https://orcid.org/0000-0001-9416-2737, Caputo, Antonella and Appay, Victor
2018.
Naïve CD8+ T-cells engage a versatile metabolic program upon activation in humans and differ energetically from memory CD8+ T-cells.
Frontiers in Immunology
9
, -.
10.3389/fimmu.2018.02736
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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.
| Item Type: | Article |
|---|---|
| Date Type: | Publication |
| Status: | Published |
| Schools: | Schools > Medicine |
| Publisher: | Frontiers Media |
| ISSN: | 1664-3224 |
| Date of First Compliant Deposit: | 22 January 2019 |
| Date of Acceptance: | 6 November 2018 |
| Last Modified: | 03 May 2023 16:47 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/118588 |
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