Research Papers: Immunology:

IL-21 modulates memory and exhaustion phenotype of T-cells in a fatty acid oxidation-dependent manner

Romy Loschinski, Martin Böttcher, Andrej Stoll, Heiko Bruns, Andreas Mackensen and Dimitrios Mougiakakos _

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Oncotarget. 2018; 9:13125-13138. https://doi.org/10.18632/oncotarget.24442

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Romy Loschinski1, Martin Böttcher1, Andrej Stoll1, Heiko Bruns1, Andreas Mackensen1 and Dimitrios Mougiakakos1

1Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany

Correspondence to:

Dimitrios Mougiakakos, email: [email protected]

Keywords: Interleukin-21; Interleukin-2; T-cell metabolism; memory T-cell; PD-1

Received: July 19, 2017     Accepted: February 01, 2018     Published: February 07, 2018


T-cell-based therapies represent a promising strategy for cancer treatment. In this context, cytokines are discussed as a bona fide instrument for fine-tuning T- cell biology. One promising candidate is the pleiotropic interleukin-21 (IL-21) with only little being known regarding its direct effects on human T-cells. Thus, we sought out to characterize the impact of IL-21 on T-cell metabolism, fitness, and differentiation. Culturing T-cells in presence of IL-21 elicited a metabolic skewing away from aerobic glycolysis towards fatty acid oxidation (FAO). These changes of the metabolic framework were paralleled by increased mitochondrial fitness and biogenesis. However, oxidative stress levels were not increased but rather decreased. Furthermore, elevated FAO and mitochondrial biomass together with enhanced antioxidative properties are linked to formation of longer lasting memory responses and less PD-1 expression. We similarly observed an IL-21-triggered induction of central memory-like T-cells and reduced levels of PD-1 on the cell surface. Taken together, IL-21 shifts T-cells towards an immunometabolic phenotype that has been associated with increased survivability and enhanced anti-tumor efficacy. In addition, our data reveals a novel interconnection between fatty acid metabolism and immune function regulated by IL 21.

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