Regulatory T cell induction by mesenchymal stem cells depends on the expression of TNFR2 by T cells.

Published on Dec 10, 2020in Stem Cell Research & Therapy5.116
· DOI :10.1186/S13287-020-02057-Z
Sina Naserian10
Estimated H-index: 10
(French Institute of Health and Medical Research),
Sara Shamdani3
Estimated H-index: 3
(French Institute of Health and Medical Research)
+ 1 AuthorsGeorges Uzan35
Estimated H-index: 35
(French Institute of Health and Medical Research)
Sources
Abstract
Mesenchymal stem/stromal cells can modulate the effector immune cells especially T lymphocytes. Due to this important feature, they can regulate the development of a variety of disorders including inflammatory and autoimmune disorders, cancers, and transplantation outcomes. One of the most important MSC immunoregulatory functions is their capacity to convert conventional T cells into regulatory T cells. Several mechanisms, mostly related to MSCs but not T cells, have been shown essential for this aspect. The inflammatory microenvironment majorly caused by pro-inflammatory cytokines has been demonstrated to govern the direction of the immune response. In this respect, we have recently revealed that the TNFα-TNFR2 signaling controls several aspects of MSC immunomodulatory properties including their ability to suppress T cells and their conversion towards Foxp3-expressing Tregs. Here in this work, we have looked from another angle by investigating the impact of TNFR2 expression by T cells on their ability to be converted to suppressive Tregs by MSCs. We showed that unlike WT-T cells, their TNFR2 KO counterparts are remarkably less able to convert into Foxp3+ and Foxp3- Tregs. Furthermore, TNFR2 blockade diminished the anti-inflammatory cytokine secretion by iTregs and consequently resulted in less T cell immunosuppression. This work is the first evidence of the crucial association of TNFR2 expression by T cells with their iTreg conversion capacity by MSCs. It strengthens once more the potential of anti-TNFR2 administration for a strong and effective interference with the immunosuppression exerted by TNFR2-expressing cells.
References15
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#1Yu Y (Peking Union Medical College)H-Index: 1
#2Valderrama Av (French Institute of Health and Medical Research)H-Index: 1
Last. Estelle Oberlin (French Institute of Health and Medical Research)H-Index: 7
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Mesenchymal stem cells (MSCs) exhibit active abilities to suppress or modulate deleterious immune responses by various molecular mechanisms. These cells are the subject of major translational efforts as cellular therapies for immune-related diseases and transplantations. Plenty of preclinical studies and clinical trials employing MSCs have shown promising safety and efficacy outcomes and also shed light on the modifications in the frequency and function of regulatory T cells (T regs). Neverthele...
1 CitationsSource
#1Mahsa Nouri Barkestani (French Institute of Health and Medical Research)H-Index: 2
#2Sara Shamdani (French Institute of Health and Medical Research)H-Index: 3
Last. Sina Naserian (French Institute of Health and Medical Research)H-Index: 10
view all 7 authors...
BACKGROUND Bone marrow derived endothelial progenitor cells (EPCs) are immature endothelial cells (ECs) involved in neo-angiogenesis and endothelial homeostasis and are considered as a circulating reservoir for endothelial repair. Many studies showed that EPCs from patients with cardiovascular pathologies are impaired and insufficient; hence, allogenic sources of EPCs from adult or cord blood are considered as good choices for cell therapy applications. However, allogenic condition increases the...
4 CitationsSource
#1Sina Naserian (French Institute of Health and Medical Research)H-Index: 10
#2Mathieu Leclerc (French Institute of Health and Medical Research)H-Index: 6
Last. Georges Uzan (French Institute of Health and Medical Research)H-Index: 35
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Graft versus host disease (GVHD) is one of the main causes of mortality and the reason for up to 50 % of morbidity after hematopoietic stem cell transplantations (HSCT) which is the treatment of choice for many blood malignancies. Thanks to years of research and exploration, we have acquired a profound understanding of the pathophysiology and immunopathology of these disorders. This led to the proposition and development of many therapeutic approaches during the last decades, some of them with v...
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#1Ghada Beldi (French Institute of Health and Medical Research)H-Index: 2
#2Sheyda Bahiraii (University of Vienna)H-Index: 1
Last. Sina Naserian (French Institute of Health and Medical Research)H-Index: 10
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Mesenchymal stem cells (MSCs) have drawn lots of attention as gold standard stem cells in fundamental and clinical researches during the last 20 years. Due to their tissue and vascular repair capacities, MSCs have been used to treat a variety of degenerative disorders. Moreover, MSCs are able to modulate immune cells' functions, particularly T cells while inducing regulatory T cells (iTregs). MSCs are very sensitive to inflammatory signals. Their biological functions could remarkably vary after ...
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#1Sara Shamdani (French Institute of Health and Medical Research)H-Index: 3
#2Georges Uzan (French Institute of Health and Medical Research)H-Index: 35
Last. Sina Naserian (French Institute of Health and Medical Research)H-Index: 10
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Stem cells have a vast range of functions from tissue regeneration to immunoregulation. They have the ability to modulate immune responses and change the progression of different inflammatory and autoimmune disorders. Tumor cells share many characteristics of stem/progenitor cells too. Both can inhibit effector T cells and other immune cells, while inducing regulatory T cells (T regs), thus, reducing the production of pro-inflammatory cytokines and increasing the production of anti-inflammatory ...
3 CitationsSource
#1Ghada Beldi (French Institute of Health and Medical Research)H-Index: 2
#2Maryam Khosravi (University of Paris)H-Index: 1
Last. Sina Naserian (French Institute of Health and Medical Research)H-Index: 10
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BACKGROUND In addition to their multilineage potential, mesenchymal stem cells (MSCs) have a broad range of functions from tissue regeneration to immunomodulation. MSCs have the ability to modulate the immune response and change the progression of different inflammatory and autoimmune disorders. However, there are still many challenges to overcome before their widespread clinical administration including the mechanisms behind their immunoregulatory function. MSCs inhibit effector T cells and oth...
12 CitationsSource
#1Sina Naserian (French Institute of Health and Medical Research)H-Index: 10
#2Mohamed Essameldin Abdelgawad (Helwan University)H-Index: 7
Last. Georges Uzan (French Institute of Health and Medical Research)H-Index: 35
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BACKGROUND Endothelial progenitor cells (EPCs) are non-differentiated endothelial cells (ECs) present in blood circulation that are involved in neo-vascularization and correction of damaged endothelial sites. Since EPCs from patients with vascular disorders are impaired and inefficient, allogenic sources from adult or cord blood are considered as good alternatives. However, due to the reaction of immune system against allogenic cells which usually lead to their elimination, we focused on the exa...
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#1Maryam Khosravi (Razi University)H-Index: 5
#1Maryam Khosravi (Razi University)H-Index: 6
Last. Mohammad Hossein Karimi (Shiraz University of Medical Sciences)H-Index: 17
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Mesenchymal stem cells (MSCs) are known for their ability to induce the conversion of conventional T cells (Tconvs) into induced regulatory T cells (iTregs) in specific inflammatory contexts. Stable Foxp3 expression plays a major role in the phenotypic and functional stability of iTregs. However, how MSCs induce stable Foxp3 expression remains unknown. We first investigated the role of cell–cell contact and cytokine secretion by bone marrow-derived MSCs (BM-MSCs) on the induction, stability, and...
19 CitationsSource
BACKGROUND: Mesenchymal stem cells (MSCs) may serve as immunoregulators by producing various anti-inflammatory molecules. Under sufficient level of TNF-α, MSCs become activated and adopt immune-suppressive phenotype (MSCs type-2) by releasing various anti-inflammatory molecule including TGF-β and IL-10. However, the ability of MSC itself to produce IL-10 under TNF-α stimulation and the correlation of TGF-β production of MSCs to IL-10 level remains to be elucidated. AIM: In this study, MSCs were ...
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#1Maryam Khosravi (Razi University)H-Index: 5
#1Maryam Khosravi (Razi University)H-Index: 6
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Among the particular immunomodulation properties of mesenchymal stem cells (MSCs), one relies on their capacity to regulatory T cell (Treg) induction from effector T cells. Stable expression of Foxp3 has a dominant role in suppressive phenotype and stability of induced regulatory T cells (iTregs). How MSCs induce stable Foxp3 expression in iTregs remains unknown. We previously showed MSCs could enhance demethylation of Treg-specific demethylated region (TSDR) in iTregs in cell-cell contact manne...
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Differences and similarities between mesenchymal stem cell and endothelial progenitor cell immunoregulatory properties against T cells
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Immune checkpoint inhibitors (ICIs), including anti-CTLA-4 (cytotoxic T lymphocyte antigen-4) and anti-PD-1/PD-L1 (programmed death-1/programmed death-ligand 1), represent a turning point in the cancer immunotherapy. However, only a minor fraction of patients could derive benefit from such therapy. Therefore, new strategies targeting additional immune regulatory mechanisms are urgently needed. CD4+Foxp3+ regulatory T cells (Tregs) represent a major cellular mechanism in cancer immune evasion. Th...
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