Mesenchymal Stromal Cell Secretion of Programmed Death-1 Ligands Regulates T Cell Mediated Immunosuppression.
Mesenchymal stromal cells (MSCs) exert broad immunosuppressive potential, modulating the activity of cells of innate and adaptive immune systems. As MSCs become accepted as a therapeutic option for the treatment of immunological disorders such as Graft versus Host Disease, our need to understand the intricate details by which they exert their effects is crucial. Programmed death-1 (PD-1) is an important regulator in T cell activation and homeostatic control. It has been reported that this pathway may be important in contact-dependent mediated immunomodulation by MSCs. The aim of this study was to establish whether MSCs, in addition to their cell-surface expression, are able to secrete PD-1 ligands (PD-L1 and PD-L2) and their potential importance in modulating contact-independent mechanisms of MSC immunosuppression. Here we report that MSCs express and secrete PD-L1 and PD-L2 and that this is regulated by exposure to interferon γ and tumor necrosis factor α. MSCs, via their secretion of PD-1 ligands, suppress the activation of CD4+ T cells, downregulate interleukin-2 secretion and induce irreversible hyporesponsiveness and cell death. Suppressed T cells demonstrated a reduction in AKT phosphorylation at T308 and a subsequent increase in FOXO3 expression that could be reversed with blockade of PD-L1. In conclusion, we demonstrate for the first time, that MSCs are able to secrete PD-1 ligands, with this being the first known report of a biological role for PD-L2 in MSCs. These soluble factors play an important role in modulating immunosuppressive effects of MSCs directly on T cell behavior and induction of peripheral tolerance. Stem Cells 2017;35:766-776.
Center for Hematology and Regenerative Medicine (HERM).|Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine.
Lindsay C
LC
Davies
Center for Hematology and Regenerative Medicine (HERM).|Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine.
Nina
N
Heldring
Center for Hematology and Regenerative Medicine (HERM).|Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
Nadir
N
Kadri
Center for Hematology and Regenerative Medicine (HERM).|Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine.
Katarina
K
Le Blanc
D017209:Apoptosis; D060890:B7-H1 Antigen / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D007165:Immunosuppression Therapy; D007376:Interleukin-2 / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation; D020543:Proteome / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D012995:Solubility; D013601:T-Lymphocytes / Q000276:immunology*
D060890:B7-H1 Antigen; C423236:CD274 protein, human; D007376:Interleukin-2; D008024:Ligands; D020543:Proteome; D051057:Proto-Oncogene Proteins c-akt
Adult human bone marrow; Adult stem cells; Cytokines; Immunomodulation; Marrow stromal stem cells; Programmed-death 1; T cells
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