PD1-mediated mesenchymal stem cells immunemodulation: the two sides of the coin

According to the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy, Mesenchymal Stem Cells (MSC) are defined as multipotent mesenchymal cells that can be found in several disparate tissues and can differentiate into osteoblasts, adipocytes, and chondroblasts, under appropriate culture conditions.1,2 The first evidences that MSC can have immunomodulatory properties were published more than a decade ago.3,4 followed by the first successful report of cell therapy with MSC for Graft Versus Host Disease (GVHD) in human.5 Within the Immune System, MSC act on the innate response by hampering the proliferation and activation of macrophages and Natural Killer (NK) cells, and on the adaptive immunity blocking the proliferation and activation of T and B lynphocytes.3,4 MSC immunosuppressant function is due to the redundant combination of secreted factors and membrane receptors engaged in cell-to-cell contact. Activated MSC produce several inhibitory cytokines, such as Transforming Growth Factor β (TGFβ), Hepatocyte Growth Factor (HGF), Indole amine 2,3-dioxygenase (IDO), Nitric Oxide (NO), Human Leukocyte Antigen G5 (HLA G5), Prostaglandin E2 (PGE2), and Interleukin 10 (IL10). They express also the inhibitory receptors Cytotoxic T-Lymphocyte Antigen 4 (CTLA4), HLA-G1, Vascular and Intercellular Cell Adeshion Molecule 1 (VCAM1 and ICAM1), and PD1/PD-Ligand 1 (PD-L1).3,4