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Front. Immunol. | doi: 10.3389/fimmu.2018.02736

Human Naïve CD8+ T-Cells Show Different Energetic Requirements Compared to Memory Cells and Engage Into a Versatile Metabolic Program Upon Activation

 Francesco Nicoli1, 2*,  Laura Papagno1,  Justin J. Frere3,  Mariela P. Cabral-Piccin1,  Emmanuel Clave4, 5, Emma Gostick6,  Antoine Toubert4, 5, David A. Price6, Antonella Caputo2 and  Victor Appay1, 7*
  • 1INSERM U1135 Centre d'Immunologie et de Maladies Infectieuses, France
  • 2Dipartimento di Medicina Molecolare, Università di Padova, Italy
  • 3University of Arizona Medical Center, United States
  • 4Institut Universitaire Hématologie (IUH), Université Paris Diderot, France
  • 5INSERM U1160 Alloimmunité Autoimmunité Transplantation, France
  • 6Institute of Infection and Immunity, Cardiff University School of Medicine, United Kingdom
  • 7International Research Center of Medical Sciences (IRCMS), Kumamoto University, Japan

Background: Characterization of the intracellular biochemical processes underlying priming of naïve CD8+ T-cells and the generation of effector and memory cells is key for our understanding of cellular immune responses and the development of immunotherapies. Studies in animal models have enlightened the metabolic processes and bioenergetics requirements that regulate the fate of distinct T-lymphocyte subpopulations. Complementing this knowledge in humans is necessary, especially as human T-lymphocyte subpopulations are defined differently, and can display distinct properties compared to mouse counterparts.
Methods: We used here different orthogonal approaches to characterize the basal and activation-induced energetic requirements of naïve and phenotypically-defined subsets of human memory CD8+ T-cells. Expression levels of genes involved in metabolic processes, nutrient flux and the role of different biochemical pathways in T-cell receptor (TCR)-induced activation were investigated.
Findings: Resting naïve CD8+ T-cells were largely quiescent, but showed a more rapid and intense upregulation of diverse energetic pathways, compared to more differentiated memory subsets, after ligation of surface-expressed TCRs. Of note, autophagy and the mTOR-dependent glycolytic pathway were simultaneously identified as critical mediators of antigen-driven priming in human naïve CD8+ T-cells. Moreover, the efficiency of naïve T-cell activation was dampened by the presence of neutral lipids and fatty acids.
Interpretation: Profound metabolic differences are apparent as a function of CD8+ T-cell lineage and differentiation status, both at rest and in response to stimulation via the T-cell receptor TCR. These observations provide a metabolic roadmap of the CD8+ T-cell compartment in humans and revealed potentially selective targets for novel immunotherapies.

Keywords: Immunometabolism, mTOR, Naïve T-cells, priming, CD8+ T-lymphocytes

Received: 24 Aug 2018; Accepted: 06 Nov 2018.

Edited by:

Loretta Tuosto, La Sapienza University of Rome, Italy

Reviewed by:

Jacques A. Nunes, INSERM U1068 Centre de recherche en cancérologie de Marseille, France
Hu Zeng, Mayo Clinic, United States  

Copyright: © 2018 Nicoli, Papagno, Frere, Cabral-Piccin, Clave, Gostick, Toubert, Price, Caputo and Appay. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
PhD. Francesco Nicoli, INSERM U1135 Centre d'Immunologie et de Maladies Infectieuses, Paris, 75013, Île-de-France, France, nclfnc1@unife.it
Prof. Victor Appay, INSERM U1135 Centre d'Immunologie et de Maladies Infectieuses, Paris, 75013, Île-de-France, France, victor.appay@upmc.fr