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Human memory CD8+ T-cells exhibit an intrinsic metabolic advantage as reflected by increased mitochondrial functionality and high glycolytic potential

Gubser, Patrick Marc. Human memory CD8+ T-cells exhibit an intrinsic metabolic advantage as reflected by increased mitochondrial functionality and high glycolytic potential. 2013, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_10487

Abstract

Intrinsic differences between na•ve and memory CD8+ T-cells affect both quality and quantity of cognate antigen response. Cellular immune function and metabolic pathways are closely linked. The metabolic repertoire of na•ve and memory T-cells remains largely unknown. Here we assessed key metabolic features of human na•ve and effector-memory CD8+ T-cells under basal, metabolic stress, and activating conditions. Basal mitochondrial respiration was similar in both subsets. Memory cells, however, possessed more complex, tubular mitochondria, and displayed greater respiratory capacity and enhanced fatty acid oxidation. Basal glycolysis was also comparable in both subsets. Memory cells, however, showed an exclusive capacity to rapidly upregulate glycolysis after mitochondrial respiration blockage. In line with this finding, effector memory CD8+ T-cells expressed more cytoplasmic GAPDH levels with enhanced activity compared to na•ve CD8+ T-cells.
Protective immunologic memory depends on antigen-experienced T-cells that are able to: (a) rapidly acquire effector function and (b) expand as secondary effector cells (Masopust and Picker, 2012). The clonal re-expansion of memory cells requires aerobic glycolysis (Warburg effect) in order to meet added biosynthetic and energetic demands (Vander Heiden et al., 2009). The metabolic requirements of rapidly responding effector memory CD8+ T-cells are unknown. Here we show that human effector memory CD8+ T-cells possess the intrinsic ability to upregulate aerobic glycolysis with unexpected rapid dynamics. In contrast to prototypical aerobic switch in activated T-cells, this early phase is insensitive to blockage of mTORC1, a known regulator of glucose metabolism in proliferating T-cells (Finlay et al., 2012; Fox et al., 2005). CD28 signaling via mTORC2 and AKT is required to sustain this early increased glycolyis. Importantly, preventing this early glycolytic phase by either blocking AKT activity or glucose deprivation, led to an impairment of IFN-gamma secretion.
Therefore, increased metabolic capacities in effector memory CD8+ T-cells promote a primed state to immediately support high glycolytic activity upon activation. This early glycolytic phase is prerequisite for immediate effector function and therefore linking metabolic features with CD8+ T-cells recall functionality.
Our findings established differential metabolic repertoires between na•ve and effector-memory CD8+ T-cells, with implications for strategies aiming to therapeutically manipulate CD8+ T-cell memory.
Advisors:Hess, Christoph
Committee Members:Rolink, Antonius G. and Palmer, Ed
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Allgemeine innere Medizin USB > Ambulante innere Medizin (Hess C)
Item Type:Thesis
Thesis no:10487
Bibsysno:Link to catalogue
Number of Pages:88 Bl.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:53
Deposited On:03 Sep 2013 09:14

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