Proinflammatory cytokines and ARDS pulmonary edema fluid induce CD40 on human mesenchymal stromal cells—A potential mechanism for immune modulation

Wilfong, Erin M.; Croze, Roxanne H.; Fang, Xiaohui; Schwede, Matthew; Niemi, Eréne C.; López, Giselle Y.; Lee, Jae Woo; Nakamura, Mary C.; Matthay, Michael A.

doi:10.1371/journal.pone.0240319

Cited by 7 publications

(7 citation statements)

References 38 publications

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“…However, apart from the production of regulatory metabolic enzymes, the repertoire of co-stimulatory and/or co-inhibitory molecules harnessing T-MSCs for immune regulation, including the role of CD40, is largely unknown. A recent study demonstrated that CD40 is upregulated on MSCs under the same conditions previously reported to induce IDO [33]. In this study, we also found that T-MSC Primed had a higher concentration of CD40 compared to T-MSC Con .…”

Section: Discussionsupporting

confidence: 87%

IDO and CD40 May Be Key Molecules for Immunomodulatory Capacity of the Primed Tonsil-Derived Mesenchymal Stem Cells

Lee

Jung

2021

IJMS

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Background: Tonsil-derived mesenchymal stem cells (T-MSCs) were reported to have suppressive effect on T cells, yet much remains unknown about the underlying mechanisms supporting this effect. We investigated the underlying mechanism of the immunomodulatory effect of T-MSCs on immune cell proliferation and cytokine production. Methods: We isolated T-MSCs from human palatine tonsil and evaluated the immunomodulatory capacity using RT-PCR, ELISA, and flow cytometry. Additionally, we assessed the expression of various soluble factors and several costimulatory molecules to detect the priming effect on T-MSCs. Results: T-MSCs significantly inhibited the immune cell proliferation and cytokine expression (TNF-α and IFN-γ) in the direct co-culture, but there was no suppressive effect in indirect co-culture. Additionally, we detected a remarkably higher expression of indoleamine 2,3-dioxygenase (IDO) in the primed T-MSCs having co-expression CD40. Moreover, immune cells or CD4+ T cells showed lower TNF-α, IFN-γ, and IL-4 expression when the primed T-MSC were added; whereas those findings were reversed when the inhibitor for IDO (not IL-4) or CD40 were added. Furthermore, T-bet and GATA3 levels were significantly decreased in the co-cultures of the primed T-MSCs and CD4+ T cells; whereas those findings were reversed when we added the neutralizing anti-CD40 antibody. Conclusions: Primed T-MSCs expressing IDO and CD40 may have immunomodulatory capacity via Th1-mediated and Th2-mediated immune response.

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Section: Discussionsupporting

confidence: 87%

IDO and CD40 May Be Key Molecules for Immunomodulatory Capacity of the Primed Tonsil-Derived Mesenchymal Stem Cells

Lee

Jung

2021

IJMS

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“…Both unprimed and IFN-γ-primed WJ-MSCs expressed MSC characteristic antigens (CD90, CD73, CD105) and lacked CD45 CD34 and CD14. As previously described [20,21], HLA-DR and CD40 expression was upregulated after IFN-γ exposure, but IFN-WJ-MSCs did not activate allogeneic T cells in coculture (data not shown). Further analyses showed that IFN-γ preexposure of WJ-MSCs upregulated the expression of PDL-1 and PDL-2 on the cell membrane and of IDO in the cytosol, while the cell surface expression of HLA-G and galectins 3 and 9 was similar between WJ-MSCs and IFN-WJ-MSCs (Fig.…”

Section: Repeated Injections Of Ifn-primed Wj-mscs Are Needed To Prot...supporting

confidence: 74%

Wharton’s jelly mesenchymal stromal cells inhibit T-cell proliferation by synergistic IDO and mitochondrial transfer mechanisms

Pochon,

Perouf,

Bertrand

et al. 2023

Preprint

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Background Wharton's jelly mesenchymal stem cells (WJ-MSCs) are multipotent stromal cells derived from the umbilical cord that may have therapeutic potential in immune-related diseases. In the context of allogeneic stem cell transplantation, WJ-MSCs represent a good candidate for graft versus host disease (GVHD) prophylaxis and treatment.Methods Herein, we investigated the immunomodulatory mechanisms of WJ-MSCs, produced at clinical grade according to our Good Manufacturing Practice, in vitro and in an experimental GVHD xenogeneic mouse model.Results We observed that repeated injections of IFN-γ-primed WJ-MSCs increased recipient survival and reduced histological GVHD scores while transiently colocalizing with T cells. We then demonstrated that WJ-MSCs were able to inhibit T-cell proliferation in vitro through indoleamine 2,3-dioxygenase (IDO) and mitochondrial transfer to T cells. Our results suggest that these processes act synergistically, since IDO is needed for the optimal effect of WJ-MSC-mediated mitochondrial transfer on T-cell metabolism, which is characterized by a switch from glycolysis toward oxidative phosphorylation.Conclusion Overall, our data indicate that IFN-γ-primed WJ-MSCs are able to control GVHD by reprogramming the metabolism of T cells, and we report for the first time a synergistic interplay between IDO and contact-dependent mitochondrial transfer, providing new insights for the treatment of immune-related diseases.

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“…Mature adipocytes have been already shown to express CD40 [20], similarly to BM-MSCs that display increased CD40 expression in response to in vitro inflammatory stimuli [28]. We reported here that ASCs also expressed CD40 in particular within inflamed WAT of obese and under stimulation by activated CD4 pos T-cell signaling in vitro.…”

Section: Discussionsupporting

confidence: 58%

CD40L-expressing CD4+ T cells prime adipose-derived stromal cells to produce inflammatory chemokines

Dulong¹,

Loisel²,

Rossille³

et al. 2022

Cytotherapy

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Proinflammatory cytokines and ARDS pulmonary edema fluid induce CD40 on human mesenchymal stromal cells—A potential mechanism for immune modulation

Cited by 7 publications

References 38 publications

IDO and CD40 May Be Key Molecules for Immunomodulatory Capacity of the Primed Tonsil-Derived Mesenchymal Stem Cells

IDO and CD40 May Be Key Molecules for Immunomodulatory Capacity of the Primed Tonsil-Derived Mesenchymal Stem Cells

Wharton’s jelly mesenchymal stromal cells inhibit T-cell proliferation by synergistic IDO and mitochondrial transfer mechanisms

CD40L-expressing CD4+ T cells prime adipose-derived stromal cells to produce inflammatory chemokines

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