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

Nicoli, Francesco, Papagno, Laura, Frere, Justin J., Cabral-Piccin, Mariela Pires, Clave, Emmanuel, Gostick, Emma, Toubert, Antoine, Price, David A., 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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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: Medicine
Publisher: Frontiers Media
ISSN: 1664-3224
Date of First Compliant Deposit: 22 January 2019
Date of Acceptance: 6 November 2018
Last Modified: 23 Jan 2019 11:00

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