Naïve CD8+ T-Cells Engage a Versatile Metabolic Program Upon Activation in Humans and Differ Energetically From Memory CD8+ T-Cells.

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

doi:10.3389/fimmu.2018.02736

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.

Highlights

CD8+ T-cells play a key role in the adaptive immune system, enabling the recognition and elimination of intracellular pathogens and various cancers [1]
Displayed low levels of granzyme B production and Tbet expression relative to MelA-specific CD8+ T-cells primed in the absence of inhibitors (Figures 4E,F). These results indicated that mechanistic target of rapamycin (mTOR) regulates naïve CD8+ T-cell priming via the glycolysis pathway [6,7,8]
We found that resting naïve CD8+ T-cells displayed lower levels of glucose uptake, lesser mitochondrial mass, and diminished uptake of fatty acids (FAs) compared with resting memory CD8+ T-cells

Summary

Introduction

CD8+ T-cells play a key role in the adaptive immune system, enabling the recognition and elimination of intracellular pathogens and various cancers [1]. In vivo mouse studies have further shown that the bioenergetics of CD8+ T-cell activation vary as a function of antigen exposure [9], suggesting that metabolic reprogramming is regulated across the differentiation spectrum via cognate engagement of surface-expressed T-cell receptors (TCRs). To consolidate this paradigm, especially in light of current efforts to augment immune efficacy using nutrient-based strategies [10, 11], it is necessary to extend these studies into humans [8, 12,13,14]. The metabolic determinants of antigendriven activation and differentiation remain poorly defined, especially in humans

Methods

Results

Conclusion