Multipotent adult progenitor cells induce regulatory T cells and promote their suppressive phenotype via TGFβ and monocyte-dependent mechanisms

• Published in: Scientific reports Vol. 11; no. 1; p. 13549
• Main Authors: Valentin-Torres, Alice, Day, Cora, Taggart, Jennifer M., Williams, Nicholas, Stubblefield, Samantha R., Roobrouck, Valerie D., Beyens, Jelle, Ting, Anthony E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30-06-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/1619/554/1898/1271; 631/250/2504/342; 631/532/2118; Adenosine; Antigens; Apoptosis; Bone marrow; CD14 antigen; CD4 antigen; CD45RA antigen; Cell activation; Cell differentiation; Cell proliferation; Cerebral infarction; CTLA-4 protein; Cytokines; Cytotoxicity; Dioxygenase; Genotype & phenotype; Graft versus host disease; Graft-versus-host reaction; Growth factors; Heart attacks; Histocompatibility antigen HLA; Humanities and Social Sciences; Hypoxia; Immune system; Immunoregulation; Inflammation; Ischemia; Ligands; Lymphocytes; Lymphocytes T; Monocytes; multidisciplinary; Myocardial infarction; PD-L1 protein; Phenotypes; Progenitor cells; Proteins; Respiratory distress syndrome; Science; Science (multidisciplinary); Stem cells; Stroke; Transforming growth factor-b
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-93025-x

Dysregulation of the immune system can initiate chronic inflammatory responses that exacerbate disease pathology. Multipotent adult progenitor cells (MAPC cells), an adult adherent bone-marrow derived stromal cell, have been observed to promote the resolution of uncontrolled inflammatory responses in a variety of clinical conditions including acute ischemic stroke, acute myocardial infarction (AMI), graft vs host disease (GvHD), and acute respiratory distress syndrome (ARDS). One of the proposed mechanisms by which MAPC cells modulate immune responses is via the induction of regulatory T cells (Tregs), however, the mechanism(s) involved remains to be fully elucidated. Herein, we demonstrate that, in an in vitro setting, MAPC cells increase Treg frequencies by promoting Treg proliferation and CD4
+
T cell differentiation into Tregs. Moreover, MAPC cell-induced Tregs (miTregs) have a more suppressive phenotype characterized by increased expression of CTLA-4, HLA-DR, and PD-L1 and T cell suppression capacity. MAPC cells also promoted Treg activation by inducing CD45RA
+
CD45RO
+
transitional Tregs. Additionally, we identify transforming growth factor beta (TGFβ) as an essential factor for Treg induction secreted by MAPC cells. Furthermore, inhibition of indoleamine 2, 3-dioxygenase (IDO) resulted in decreased Treg induction by MAPC cells demonstrating IDO involvement. Our studies also show that CD14
+
monocytes play a critical role in Treg induction by MAPC cells. Our study describes MAPC cell dependent Treg phenotypic changes and provides evidence of potential mechanisms by which MAPC cells promote Treg differentiation.