HLA-G is a Crucial Immunosuppressive Molecule Secreted by Adult Human Mesenchymal Stem Cells

Selmani, Zohair; Naji, Abderrahim; Gaiffe, Émilie; Obert, L.; Tiberghien, Pierre; Rouas‐Freiss, Nathalie; Carosella, Edgardo D.; Deschaseaux, Frédéric

doi:10.1097/tp.0b013e3181a2a4b3

Cited by 131 publications

(89 citation statements)

References 22 publications

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“…We specifically examined the correlation between MSC licensing and T cell cytokine suppression with MSC expression of galectin-9 (34), TRAIL (35), HLAG (36), TNFR (37), SLAM2 (38), HLAC (39), OX40L (40), CD200R (41), FASL (42), and B7H1/B7DC (26). Among these, we identified and validated B7H1 and B7DC as the sole inhibitory contact factors deployed by IFN-g licensing (26).…”

Section: Discussionmentioning

confidence: 99%

IDO-Independent Suppression of T Cell Effector Function by IFN-γ–Licensed Human Mesenchymal Stromal Cells

Chinnadurai

Copland

Patel

et al. 2014

The Journal of Immunology

231

214

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Human bone marrow–derived mesenchymal stromal cells (MSCs) inhibit proliferation of activated T cells, and IFN-γ plays an important role in this process. This IFN-γ–licensed veto property is IDO-dependent. To further decipher the mechanistic underpinnings of MSC veto function on T cells, we investigated the effect of MSCs and IFN-γ–licensed MSCs on T cell effector function as assayed by cytokine secretion of T cells. Although MSCs and IFN-γ–licensed MSCs inhibit T cell proliferation, only IFN-γ–licensed MSCs significantly inhibit Th1 cytokine (IFN-γ, TNF-α, and IL-2) production by T cells. Additionally, IFN-γ–licensed MSCs inhibit T cell degranulation as well as single, double, and triple cytokine–producing T cells. Although IFN-γ–licensed MSCs upregulate their IDO activity, we found that MSC IDO catalytic function is dispensable with regard to MSC-driven inhibition of T cell effector function. Novel flow cytometry based functional screening of MSC-expressed, IFN-γ–licensed inhibitory molecules identified B7H1 and B7DC/PD1 pathways as essential effectors in blocking T cell function. Small interfering RNA–mediated blocking of B7H1 and B7DC reverses the inhibitory potential of IFN-γ–licensed MSCs on T cell effector function. Mechanistic analysis revealed that clustering of MHC and coinhibitory molecules are indispensable for the inhibitory effect of IFN-γ MSCs. Although exogenous IL-2 reverses B7H1-Ig–mediated inhibition of T cell proliferation, it does not affect the veto function of IFN-γ MSCs on both T cell proliferation and effector function. Our results reveal a new immunosuppressive property of IFN-γ–licensed MSCs that inhibits T cell effector function independent of IDO but through the ligands for PD1.

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Section: Discussionmentioning

confidence: 99%

IDO-Independent Suppression of T Cell Effector Function by IFN-γ–Licensed Human Mesenchymal Stromal Cells

Chinnadurai

Copland

Patel

et al. 2014

The Journal of Immunology

231

214

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“…[16][17][18] However, the precise mechanisms underlying MSC-mediated immunosuppression remain largely undefined. Soluble factors such as hepatocyte growth factor (HGF), transforming growth factor (TGF)-β, 19,20 indoleamine 2,3-dioxygenase (IDO), 21 IL-2 and IL-10, 22 prostaglandin E2 (PGE2), [23][24][25] soluble HLA-G, 26 nitric oxide (NO), 27 immune cells (regulatory T cells), 28 as well as contact dependent mechanisms, 29,30 have been involved in MSC-mediated immunosuppression. In a previous study 8 we demonstrated that CD271-MSCs elicited a potent allosuppression even at low concentrations, and that the majority of the immunosuppressive effect of CD271-MSC haematologica | 2013; 98(10) is mediated via PGE2, but not via HLA-G, NO or IL-10 molecules.…”

Section: Discussionmentioning

confidence: 99%

Clonal analysis of multipotent stromal cells derived from CD271+ bone marrow mononuclear cells: functional heterogeneity and different mechanisms of allosuppression

Kuçi¹,

Seiberth²,

Latifi-Pupovci³

et al. 2013

Haematologica

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Previous reports demonstrated a relationship between proliferation potential and trilineage differentiation in mesenchymal stromal cell-derived clones generated using plastic adherence (PA-MSCs). However, there are no reports presenting a clonal analysis of the proliferative potential, differentiation potential and allosuppressive effects of human mesenchymal stromal cell subsets. In this study, we performed a clonal analysis of mesenchymal stromal cells generated from human CD271 + bone marrow mononuclear cells (CD271-MSCs). After transfection with the gene encoding green fluorescent protein, the cells were single-cell sorted and cultured for 2-4 weeks. A population doubling analysis demonstrated that 25% of CD271-MSC clones are fast-proliferating clones compared to only 10% of PA-MSC clones. Evaluation of the allosuppressive potential demonstrated that 81.8% of CD271-MSC clones were highly allosuppressive compared to only 58% of PA-MSC clones. However, no consistent correlation was observed between allosuppression and proliferative potential. Prostaglandin E2 levels were positively correlated with the allosuppressive activity of individual clones, suggesting that this molecule may be a useful predictive biomarker for the allosuppressive potential of mesenchymal stromal cells. In contrast, inhibitory studies of indoleamine 2,3 dioxygenase indicated that none of the clones used this enzyme to mediate their allosuppressive effect. Differentiation studies revealed the presence of tripotent, bipotent and unipotent CD271-MSC and PA-MSC clones which suppressed the allogeneic reaction to differing extents in vitro. In conclusion, our findings demonstrate differences between CD271-MSCs and PA-MSCs and indicate that neither proliferation potential nor differentiation potential represents a consistent predictive parameter for the immunomodulatory effects of either type of mesenchymal stromal cells. ABSTRACT Methods Immunomagnetic selection of CD271+ bone marrow mononuclear cells and generation of CD271-mesenchymal stromal cells

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“…48 MSCs use a variety of different factors in order to suppress immune responses, many of which are secreted. Some of these factors are constitutively produced by MSCs, such as HLA-G5, 49 prostaglandin E 2 (PGE 2 ), 50 and galectins. 51 The immunomodulatory effects exerted by MSCs can be augmented if the cells are activated by cytokines such as IFN-g. [52][53][54] It has also been shown that MSCs can be activated by stimulation of their Toll-like receptors.…”

Section: Immune Modulation By Mscsmentioning

confidence: 99%

Stromal cells–are they really useful for GVHD?

Kaipe

Erkers

Sadeghi

et al. 2014

Bone Marrow Transplant

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Mesenchymal stromal cells (MSCs) have immunomodulatory effects and are increasingly being used for the treatment of acute and chronic GVHD. Although they seem immuno-privileged, they induce alloresponses, but the risk of immunization is poorly characterized. After infusion, they first reach the lungs, liver and spleen, and are then difficult to trace. Several mechanisms are involved in stromal cells suppressing alloreactivity, such as induction of regulatory T cells, but whether or not this will also affect leukemic relapse or increase infections is not known. Although several encouraging pilot studies have been published, there have been few prospective randomized trials. There may be a bias in the literature, as negative results are seldom published, and there have been few comparative studies with other immunosuppressive regimens. Most animal models have failed to show any effect on GVHD. Several questions remain to be answered for optimization of stromal cell therapy. Which source is optimal-BM, fat, cord or decidua? Can stromal cells be replaced by exosomes, which culture conditions are most appropriate and at what passage and how frequently should cells be administered? More research is required to move stromal cell therapy forward to become an established treatment for acute and chronic GVHD.

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HLA-G is a Crucial Immunosuppressive Molecule Secreted by Adult Human Mesenchymal Stem Cells

Cited by 131 publications

References 22 publications

IDO-Independent Suppression of T Cell Effector Function by IFN-γ–Licensed Human Mesenchymal Stromal Cells

IDO-Independent Suppression of T Cell Effector Function by IFN-γ–Licensed Human Mesenchymal Stromal Cells

Clonal analysis of multipotent stromal cells derived from CD271+ bone marrow mononuclear cells: functional heterogeneity and different mechanisms of allosuppression

Stromal cells–are they really useful for GVHD?

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