AUTHOR=Behm Christian , Blufstein Alice , Gahn Johannes , Moritz Andreas , Rausch-Fan Xiaohui , Andrukhov Oleh 

TITLE=25-hydroxyvitamin D3 generates immunomodulatory plasticity in human periodontal ligament-derived mesenchymal stromal cells that is inflammatory context-dependent

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1100041

DOI=10.3389/fimmu.2023.1100041

ISSN=1664-3224

ABSTRACT=<sec><title>Introduction</title><p>Human periodontal ligament-derived mesenchymal stromal cells (hPDL-MSCs) exhibit a tight bi-directional interaction with CD4<sup>+</sup> T lymphocytes. The hPDL-MSCs’ immunomodulatory abilities are drastically enhanced by pro-inflammatory cytokines via boosting the expression of various immunomediators. 25-hydroxyvitamin D<sub>3</sub> (25(OH)D<sub>3</sub>), the major metabolite of vitamin D3 in the blood, affects both hPDL-MSCs and CD4<sup>+</sup> T lymphocytes, but its influence on their interaction is unknown.</p></sec><sec><title>Methods</title><p>Therefore, primary hPDL-MSCs were stimulated <italic>in vitro</italic> with tumor necrosis factor (TNF)-α a or interleukin (IL)-1β in the absence and presence of 25(OH)D<sub>3</sub> followed by an indirect co-culture with phytohemagglutinin-activated CD4<sup>+</sup> T lymphocytes. The CD4<sup>+</sup> T lymphocyte proliferation, viability, and cytokine secretion were analyzed. Additionally, the expression of various immunomediators in hPDL-MSCs was investigated, and their implication was verified by using pharmacological inhibitors.</p></sec><sec><title>Results</title><p>25(OH)D<sub>3</sub> significantly counteracted the suppressive effects of IL-1β-treated hPDL-MSCs on CD4<sup>+</sup> T lymphocyte proliferation, whereas no effects were observed in the presence of TNF-α. Additionally, 25(OH)D<sub>3</sub> significantly increased the percentage of viable CD4<sup>+</sup> T lymphocytes via TNF-α- or IL-1β-treated hPDL-MSCs. It also caused a significant decrease in interferon-γ, IL-17A, and transforming growth factor-β productions, which were triggered by TNF-α-treated hPDL-MSCs. 25(OH)D<sub>3</sub> significantly decreased the production of various immunomediators in hPDL-MSCs. Inhibition of two of them, prostaglandin E2 and indoleamine-2,3-dioxygenase-1, partially abolished some of the hPDL-MSCs-mediated effects of 25(OH)D<sub>3</sub> on CD4<sup>+</sup> T lymphocytes.</p></sec><sec><title>Conclusion</title><p>These data indicate that 25(OH)D<sub>3</sub> influences the immunomodulatory activities of hPDL-MSCs. This modulatory potential seems to have high plasticity depending on the local cytokine conditions and may be involved in regulating periodontal tissue inflammatory processes.</p></sec>