Mesenchymal Stromal Cells Disrupt mTOR-Signaling and Aerobic Glycolysis During T-Cell Activation.
Mesenchymal stromal cells (MSCs) possess numerous regenerative and immune modulating functions. Transplantation across histocompatibility barriers is feasible due to their hypo-immunogenicity. MSCs have emerged as promising tools for treating graft-versus-host disease following allogeneic stem cell transplantation. It is well established that their clinical efficacy is substantially attributed to fine-tuning of T-cell responses. At the same time, increasing evidence suggests that metabolic processes control T-cell function and fate. Here, we investigated the MSCs' impact on the metabolic framework of activated T-cells. In fact, MSCs led to mitigated mTOR signaling. This phenomenon was accompanied by a weaker glycolytic response (including glucose uptake, glycolytic rate, and upregulation of glycolytic machinery) toward T-cell activating stimuli. Notably, MSCs express indoleamine-2,3-dioxygenase (IDO), which mediates T-cell suppressive tryptophan catabolism. Our observations suggest that IDO-induced tryptophan depletion interferes with a tryptophan-sufficiency signal that promotes cellular mTOR activation. Despite an immediate suppression of T-cell responses, MSCs foster a metabolically quiescent T-cell phenotype characterized by reduced mTOR signaling and glycolysis, increased autophagy, and lower oxidative stress levels. In fact, those features have previously been shown to promote generation of long-lived memory cells and it remains to be elucidated how MSC-induced metabolic effects shape in vivo T-cell immunity.
Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Germany.
Martin
M
Böttcher
Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Germany.
Andreas D
AD
Hofmann
Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Germany.
Heiko
H
Bruns
Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Germany.
Martina
M
Haibach
Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Germany.
Romy
R
Loschinski
Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Germany.
Domenica
D
Saul
Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Germany.
Andreas
A
Mackensen
Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Katarina
K
Le Blanc
Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Germany.
Regina
R
Jitschin
Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Germany.
Dimitrios
D
Mougiakakos
D005260:Female; D006019:Glycolysis / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D008213:Lymphocyte Activation; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000276:immunology*
C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
IDO; Immunometabolism; Mesenchymal stromal cells; T-cell suppression; mTOR Signaling