Cord-Blood-Derived Mesenchymal Stromal Cells Downmodulate CD4<sup>+</sup>T-Cell Activation by Inducing IL-10-Producing Th1 Cells

Selleri, Silvia; Dieng, Mame Massar; Nicoletti, Simon; Louis, Isabelle; Beauséjour, Christian; Deist, Françoise Le; Haddad, Élie

doi:10.1089/scd.2012.0315

Cited by 37 publications

(33 citation statements)

References 52 publications

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“…Nevertheless, an effective suppression of T cell function, mediated by the induction of IL‐10 expression in IFNγ‐producing T cells (Th1 cells), was achieved. In fact, UCB‐MSCs increased the percentage of CD4 + IFNγ + IL‐10 + T cells without changing the frequency of CD4 + CD25 ++ FoxP3 + Treg cells, demonstrating that MSCs may employ other mechanisms than Treg induction to negatively regulate T cell activity (Selleri et al, ). In the same line, our results show that IL‐10 mRNA expression is induced in both CD4 + and CD8 + T cells after 24 hr of exposure to BM‐MSCs.…”

Section: Discussionmentioning

confidence: 99%

Immunomodulatory effect of human bone marrow‐derived mesenchymal stromal/stem cells on peripheral blood T cells from rheumatoid arthritis patients

Pedrosa

Gomes

Laranjeira

et al. 2019

J Tissue Eng Regen Med

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Rheumatoid arthritis (RA) is a Th1/Th17‐mediated autoimmune disease whose current treatment, consisting in the blockage of inflammatory cytokines by disease‐modifying antirheumatic drugs, is not effective for all patients. The therapeutic potential of mesenchymal stromal/stem cells' (MSCs) immunomodulatory properties is being explored in RA. Here, we investigate the effect of human bone marrow (BM)‐MSCs on the expression of cytokines involved in RA physiopathology by the distinct functional compartments of CD4+ and CD8+ T cells from RA patients. Peripheral blood mononuclear cells from healthy individuals (n = 6) and RA patients (n = 12) were stimulated with phorbol myristate acetate plus ionomycin and cultured in the presence/absence of BM‐MSCs. The expression of (interleukin) IL‐2, tumor necrosis factor alpha (TNF‐α), and interferon‐gamma (IFN‐γ) was evaluated in naive, central memory, effector memory, and effector CD4+ and CD8+ T cells, whereas IL‐6, IL‐9, and IL‐17 expression was measured in total CD4+ and CD8+ T cells. mRNA expression of IL‐4, IL‐10, transforming growth factor beta (TGF‐β), cytotoxic T‐lymphocyte‐associated antigen 4, and/or forkhead box P3 was quantified in fluorescence‐activated cell sorting‐purified CD4+ T cells, CD8+ T cells, and CD4+ Treg. BM‐MSCs inhibited the production of TNF‐α, IL‐17, IL‐6, IL‐2, IFN‐γ, and IL‐9 by T cells from RA patients, mainly by reducing the percentage of cells producing cytokines. This inhibitory effect was transversal to all T cell subsets analyzed. At mRNA level, BM‐MSCs increased expression of IL‐10 and TGF‐β by CD4+ and CD8+ T cells. BM‐MSCs displayed a striking inhibitory action over T cells from RA patients, reducing the expression of cytokines involved in RA physiopathology. Remarkably, BM‐MSC‐derived immunomodulation affected either naive, effector, and memory T cells.

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Section: Discussionmentioning

confidence: 99%

Immunomodulatory effect of human bone marrow‐derived mesenchymal stromal/stem cells on peripheral blood T cells from rheumatoid arthritis patients

Pedrosa

Gomes

Laranjeira

et al. 2019

J Tissue Eng Regen Med

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“…In vitro, Tregs are able to suppress the proliferation of T cells triggered by specific antigens or polyclonal TCR stimulators (such as anti-CD3 mAb) in the presence of antigen-presenting cells (APCs) by a granzyme-dependent or perforin-dependent mechanism or to deliver a negative signal to responder T cells [12]. However, whether the immunosuppressive effect of UC-MSCs on the proliferation of activated T cells is due to the induced conversion of effecter T cells into Tregs is controversial [6,13]. For example, S. Selleri et al suggest that it may not be the FoxP3 + Tregs but the IL-10 producing Th1 cells induced by UC-MSCs that have contributed to the suppression of activated PBMCs.…”

Section: Introductionmentioning

confidence: 99%

“…For example, S. Selleri et al suggest that it may not be the FoxP3 + Tregs but the IL-10 producing Th1 cells induced by UC-MSCs that have contributed to the suppression of activated PBMCs. [13].…”

Section: Introductionmentioning

confidence: 99%

Human umbilical cord-derived mesenchymal stem cells suppress proliferation of PHA-activated lymphocytes in vitro by inducing CD4+CD25highCD45RA+ regulatory T cell production and modulating cytokine secretion

Yang

Sun

et al. 2016

Cellular Immunology

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Bone marrow-derived mesenchymal stem cells (MSCs) are promising candidate cells for therapeutic application in autoimmune diseases due to their immunomodulatory properties. Unused human umbilical cords (UC) offer an abundant and noninvasive source of MSCs without ethical issues and are emerging as a valuable alternative to bone marrow tissue for producing MSCs. We thus investigated the immunomodulation effect of umbilical cord-derived MSCs (UC-MSCs) on human peripheral blood mononuclear cells (PBMCs), T cells in particular, in a co-culture system. We found that UC-MSCs efficiently suppressed the proliferation of phytohaemagglutinin (PHA)-stimulated PBMCs (p<0.01). Kinetic analysis revealed that UC-MSCs primarily inhibited the division of generation 3 (G3) and 4 (G4) of PBMCs. In addition, UC-MSCs augmented the expression of CD127(+) and CD45RA(+) but reduced the expression of CD25(+) in PBMCs stimulated by PHA (p<0.05). Furthermore, UC-MSCs inhibited PHA-resulted increase in the frequency of CD4(+)CD25(+)CD127(low/-) Tregs significantly (p<0.01) but augmented PHA-resulted increase in the frequency of CD4(+)CD25(high)CD45RA(+) Tregs to about three times in PBMCs. The levels of anti-inflammatory cytokines, PEG2, TGF-β, and IL-10 were greatly up-regulated, accompanied by a significant down-regulation of pro-inflammatory IFN-γ in the co-culture (p<0.01). Our results showed that UC-MSCs are able to suppress mitogen-induced PBMC activation and proliferation in vitro by altering T lymphocyte phenotypes, increasing the frequency of CD4(+)CD25(high)CD45RA(+) Tregs, and modulating the associated cytokine production. Further studies are warranted to investigate the therapeutic potential of UC-MSCs in immunologically-diseased conditions.

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“…In line with this study, the capacity of MSCs to induce CD4 + CD25 high Foxp3 + regulatory T cells from CD4 + T cells differentiating into Th1 and Th17 cells has been shown [17]. Similarly, MSCs direct the conversion of Th17 cells into Treg cells through an IL-17A + FoxP3 + double-positive phenotype [103] and the generation of a Th1 producing IL-10 cells [104]. The capacity of MSCs to inhibit proinflammatory Th1 and Th17 cells and to induce Treg cells has been demonstrated using several experimental mouse models.…”

Section: Adaptive Immunity In Ra and The Effect Of Mscsmentioning

confidence: 65%

Mesenchymal Stem Cells Regulate the Innate and Adaptive Immune Responses Dampening Arthritis Progression

Contreras-López

Figueroa

Djouad

et al. 2016

Stem Cells International

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Mesenchymal stem cells (MSCs) are multipotent stem cells that are able to immunomodulate cells from both the innate and the adaptive immune systems promoting an anti-inflammatory environment. During the last decade, MSCs have been intensively studied in vitro and in vivo in experimental animal model of autoimmune and inflammatory disorders. Based on these studies, MSCs are currently widely used for the treatment of autoimmune diseases such as rheumatoid arthritis (RA) characterized by complex deregulation of the immune systems. However, the therapeutic properties of MSCs in arthritis are still controverted. These controversies might be due to the diversity of MSC sources and isolation protocols used, the time, the route and dose of MSC administration, the variety of the mechanisms involved in the MSCs suppressive effects, and the complexity of arthritis pathogenesis. In this review, we discuss the role of the interactions between MSCs and the different immune cells associated with arthritis pathogenesis and the possible means described in the literature that could enhance MSCs therapeutic potential counteracting arthritis development and progression.

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Cord-Blood-Derived Mesenchymal Stromal Cells Downmodulate CD4⁺T-Cell Activation by Inducing IL-10-Producing Th1 Cells

Cited by 37 publications

References 52 publications

Immunomodulatory effect of human bone marrow‐derived mesenchymal stromal/stem cells on peripheral blood T cells from rheumatoid arthritis patients

Immunomodulatory effect of human bone marrow‐derived mesenchymal stromal/stem cells on peripheral blood T cells from rheumatoid arthritis patients

Human umbilical cord-derived mesenchymal stem cells suppress proliferation of PHA-activated lymphocytes in vitro by inducing CD4+CD25highCD45RA+ regulatory T cell production and modulating cytokine secretion

Mesenchymal Stem Cells Regulate the Innate and Adaptive Immune Responses Dampening Arthritis Progression

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Cord-Blood-Derived Mesenchymal Stromal Cells Downmodulate CD4+T-Cell Activation by Inducing IL-10-Producing Th1 Cells

Cited by 37 publications

References 52 publications

Immunomodulatory effect of human bone marrow‐derived mesenchymal stromal/stem cells on peripheral blood T cells from rheumatoid arthritis patients

Immunomodulatory effect of human bone marrow‐derived mesenchymal stromal/stem cells on peripheral blood T cells from rheumatoid arthritis patients

Human umbilical cord-derived mesenchymal stem cells suppress proliferation of PHA-activated lymphocytes in vitro by inducing CD4+CD25highCD45RA+ regulatory T cell production and modulating cytokine secretion

Mesenchymal Stem Cells Regulate the Innate and Adaptive Immune Responses Dampening Arthritis Progression

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Cord-Blood-Derived Mesenchymal Stromal Cells Downmodulate CD4⁺T-Cell Activation by Inducing IL-10-Producing Th1 Cells