Mesenchymal Stromal Cells Inhibit Aerobic Glycolysis in Activated T Cells by Negatively Regulating Hexokinase II Activity Through PD-1/PD-L1 Interaction

• Published in: Transplantation and cellular therapy 2021-03, Vol.27 (3), p.231.e1-231.e8
• Main Authors: Kawasaki, Yasufumi, Sato, Kazuya, Mashima, Kiyomi, Nakano, Hirofumi, Ikeda, Takashi, Umino, Kento, Morita, Kaoru, Izawa, Junko, Takayama, Norihito, Hayakawa, Hiroko, Tominaga, Kaoru, Endo, Hitoshi, Kanda, Yoshinobu
• Format: Article
• Language: English
• Subjects: B7-H1 Antigen - genetics; Glycolysis; Hexokinase - genetics; Hexokinase II (HK2); Lymphocyte Activation; Mesenchymal Stem Cells; Mesenchymal stromal cell (MSC); PD-1; Programmed Cell Death 1 Receptor - genetics; T-cells; T-Lymphocytes; Tryptophan - metabolism
• ISSN: 2666-6367; 2666-6367
• DOI: 10.1016/j.jtct.2020.11.012

•Human mesenchymal stromal cells inhibit glucose uptake and its subsequent utilization in activated T cells.•Human mesenchymal stromal cells inhibit T cell glucose metabolism by negatively regulating hexokinase II protein expression through PD-1/PD-L1 interaction. Mesenchymal stromal cells (MSCs) have been shown to inhibit aerobic glycolysis in activated T cells, leading to increased autophagy. Although tryptophan depletion induced by indoleamine 2,3-dioxygenase (IDO) generated by MSCs has been suggested as a potential mechanism, we found that this inhibition was completely abolished when T cells were physically separated from MSCs using the Transwell system. Instead, in the current study, we demonstrate that programmed cell death 1 receptor (PD-1) and its ligand PD-L1, the expression of which is induced on activated T cells and MSCs, respectively, in response to IFN-γ are involved in this inhibition. Blockade of PD-1/PD-L1 interaction by blocking antibodies significantly restored glucose uptake, glycolytic activity, and cluster formation of activated T cells, whereas a specific inhibitor of IDO, 1-methyl-DL-tryptophan, had no effect. Neither surface nor cytoplasmic glucose transporter-1 expression on T cells was changed by MSCs. In addition, glycolytic gene expression in activated T cells was not inhibited despite the presence of MSCs. However, we found that hexokinase II (HK2) protein expression was markedly decreased in activated T cells that had been cocultured with MSCs. PD-1 blocking antibody restored HK2 expression. Taken together, our findings indicate that the PD-1/PD-L1 axis is involved in the MSC-mediated suppression of T cell glycolysis by negatively regulating HK2 activity at the protein level, but not at the mRNA level. [Display omitted]