Loschinksi et al. found that in vitro, IL-21 shifts the human T cell metabolism from glycolysis to fatty acid oxidation (FAO), leading to reduced levels of reactive oxygen species (ROS), senescence, and PD-1 expression, and increased mitochondrial potential and biomass. FAO metabolism promoted an increase in the central-memory T cell phenotype, while reducing the effector T cell and Treg population. IL-21 similarly reduced ROS levels and PD-1 expression in T cells derived from chronic lymphocytic leukemia patients, indicating direct potential clinical relevance.

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.

Author Info: (1) Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany. (2) Department of Internal Medicine 5, Hematology and Oncology, University of

Author Info: (1) Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany. (2) Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany. (3) Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany. (4) Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany. (5) Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany. (6) Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany.

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