Mesenchymal Stromal Cell Secretion of Programmed Death-1 Ligands Regulates T Cell Mediated Immunosuppression

Abstract

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

Clinical Use of Mesenchymal Stromal Cells in the Treatment of Acute Graft-versus-Host Disease

“…IFNγ and TNF-α are the most important T cell effector cytokines in MSC immunomodulatory effects. Davies et al [18] demonstrated that MSCs express and secrete programmed death ligands (PD-L) 1 and 2. They reported PD-L1- and PD-L2-mediated suppression of T cell proliferation by MSCs, IL-2 secretion, and induction of an irreversible hyporesponsive state, as well as apoptosis.…”

“…In vitro models indicate that MSCs induce regulatory T cells and also sustain their survival and suppressive phenotypes [19]. It is documented that MSCs affect the status of T cells and skew them towards a regulatory phenotype [18]. MSCs also interact with B cells by inhibiting B cell responses [19] which results in cell cycle arrest, decreased immunoglobulin production, and impaired chemotaxis.…”

Tumor-associated fibrosis as a regulator of tumor immunity and response to immunotherapy

“…CAFs have been shown to be suppressive, and using in vitro assays, some of these subsets like MSCs have been shown to exhibit direct immunosuppressive activities in a manner similar to regulatory T cells (T reg )[11,12]. CAFs can impair CTL activation, cytokine production, and cytotoxicity through the production of soluble factors such as IL10, TGF-β, or VEGF, as well as through metabolic reprograming via prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO), and arginase[2,13] or expression of T cell checkpoint molecules like programmed death-ligand 1 (PD-L1)[2,13].…”

Phenotypic, Transcriptional, and Functional Analysis of Liver Mesenchymal Stromal Cells and Their Immunomodulatory Properties

“…Although a blockade of PD‐L1 did not alter the overall T cell proliferative responses, it resulted in a reduced L‐MSC–induced inhibition in 6 of the 11 experiments (Fig. B), suggesting that this mechanism may play a partial role in the anti–T cell proliferative responses, likely through soluble factors . Second, PTGS1 was found to be one of most abundant RNA sequences in L‐MSCs (top 1% of all detected transcripts) and was detected at significantly higher amounts in L‐MSCs versus A‐MSCs and BM‐MSCs.…”