Immunomodulatory effects of interferon-γ on human fetal cardiac mesenchymal stromal cells

Abstract Background Mesenchymal stromal cells (MSCs), due to their regenerative and immunomodulatory properties, are therapeutically used for diseases, including heart failure. As early gestational-phase embryonic tissues exhibit extraordinary regenerative potential, fetal MSCs exposed to inflammation offer a unique opportunity to evaluate molecular mechanisms underlying preferential healing, and investigate their inherent abilities to communicate with the immune system during development. The principal aim of this study was to evaluate the effects of interferon-γ (IFNγ) on the immunomodulatory effects of first-trimester human fetal cardiac (hfc)-MSCs. Methods hfcMSCs (gestational week 8) were exposed to IFNγ, with subsequent analysis of the whole transcriptome, based on RNA sequencing. Exploration of surface-expressed immunoregulatory mediators and modulation of T cell responses were performed by flow cytometry. Presence and activity of soluble mediators were assessed by ELISA or high-performance liquid chromatography. Results Stimulation of hfcMSCs with IFNγ revealed significant transcriptional changes, particularly in respect to the expression of genes belonging to antigen presentation pathways, cell cycle control, and interferon signaling. Expression of immunomodulatory genes and associated functional changes, including indoleamine 2,3-dioxygenase activity, and regulation of T cell activation and proliferation via programmed cell death protein (PD)-1 and its ligands PD-L1 and PD-L2, were significantly upregulated. These immunoregulatory molecules diminished rapidly upon withdrawal of inflammatory stimulus, indicating a high degree of plasticity by hfcMSCs. Conclusions To our knowledge, this is the first study performing a systematic evaluation of inflammatory responses and immunoregulatory properties of first-trimester cardiac tissue. In summary, our study demonstrates the dynamic responsiveness of hfcMSCs to inflammatory stimuli. Further understanding as to the immunoregulatory properties of hfcMSCs may be of benefit in the development of novel stromal cell therapeutics for cardiovascular disease.

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Molecular Mechanisms of Immunomodulation Properties of Mesenchymal Stromal Cells: A New Insight into the Role of ICAM-1

Stem Cells International ◽

10.1155/2017/6516854 ◽

2017 ◽

Vol 2017 ◽

pp. 1-15 ◽

Cited By ~ 22

Author(s):

Yury Rubtsov ◽

Кirill Goryunov ◽

Аndrey Romanov ◽

Yulia Suzdaltseva ◽

George Sharonov ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mesenchymal Stromal Cells ◽

T Cell Activation ◽

Stromal Cells ◽

Cell Activation ◽

Molecular Mechanisms ◽

Cell Function ◽

Mixed Cultures ◽

Activated T Cells

Mesenchymal stromal cells (MSC) control excessive inflammation and create a microenvironment for tissue repair protecting from chronic inflammation and tissue fibrosis. We examined the molecular mechanisms of MSC immunomodulatory function in mixed cultures of human adipose-derived MSC with lymphocytes. Our data show that MSC promote unstimulated lymphocyte survival potentially by an increase in antigen presentation. Under inflammatory conditions, mimicked by stimulation of TCR in lymphocytes, MSC suppress activation and proliferation of stimulated T cells. Immunosuppression is accompanied by downregulation of IL-2Rαthat negatively affects the survival of activated T cells. MSC upregulate transcription of indolamine-2,3-dioxygenase (IDO) and inducible NO synthase (iNOS), which generate products negatively affecting T cell function. Both MSC and lymphocytes dramatically increase the surface ICAM-1 level in mixed cultures. Antibody-mediated blockage of surface ICAM-1 partially releases MSC-mediated immune suppression in vitro. Our data suggest that MSC have cell-intrinsic molecular programs depending on the inflammatory microenvironment. We speculate that MSC sense soluble factors and respond by surface ICAM-1 upregulation. ICAM-1 is involved in the control of T cell activation leading to immunosuppression or modest stimulation depending on the T cell status. Immunomodulation by MSC ranging from support of naive T cell survival to immunosuppression of activated T cells may affect the tissue microenvironment protecting from aberrant regeneration.

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

Stem Cells and Development ◽

10.1089/scd.2012.0315 ◽

2013 ◽

Vol 22 (7) ◽

pp. 1063-1075 ◽

Cited By ~ 24

Author(s):

Silvia Selleri ◽

Mame Massar Dieng ◽

Simon Nicoletti ◽

Isabelle Louis ◽

Christian Beausejour ◽

...

Keyword(s):

T Cell ◽

Cord Blood ◽

Mesenchymal Stromal Cells ◽

T Cell Activation ◽

Stromal Cells ◽

Cell Activation ◽

Cd4 T Cell ◽

Th1 Cells

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Thymoproteasome-Expressing Mesenchymal Stromal Cells Confer Protective Anti-Tumor Immunity via Cross-Priming of Endogenous Dendritic Cells

Frontiers in Immunology ◽

10.3389/fimmu.2020.596303 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jean-Pierre Bikorimana ◽

Nehme El-Hachem ◽

Abed El-Hakim El-Kadiry ◽

Jamilah Abusarah ◽

Natasha Salame ◽

...

Keyword(s):

T Cell ◽

Mesenchymal Stromal Cells ◽

T Cell Activation ◽

Stromal Cells ◽

Cell Activation ◽

De Novo ◽

Cd8 T Cell ◽

Effector Memory ◽

Phagocytic Cells ◽

Cell Immunity

Proteasomes are complex macromolecular structures existing in various forms to regulate a myriad of cellular processes. Besides degrading unwanted or misfolded proteins (proteostasis), distinct immune functions were ascribed for the immunoproteasome and thymoproteasome (TPr) complexes. For instance, antigen degradation during ongoing immune responses mainly relies on immunoproteasome activity, whereas intrathymic CD8 T-cell development requires peptide generation by the TPr complex. Despite these substantial differences, the functional contribution of the TPr to peripheral T-cell immunity remains ill-defined. We herein explored whether the use of mesenchymal stromal cells (MSCs) engineered to exhibit altered proteasomal activity through de novo expression of the TPr complex can be exploited as a novel anti-cancer vaccine capable of triggering potent CD8 T-cell activation. Phenotypic and molecular characterization of MSC-TPr revealed a substantial decrease in MHCI (H2-Kb and H2-Dd) expression along with elevated secretion of various chemokines (CCL2, CCL9, CXCL1, LIX, and CX3CL1). In parallel, transcriptomic analysis pinpointed the limited ability of MSC-TPr to present endogenous antigens, which is consistent with their low expression levels of the peptide-loading proteins TAP, CALR, and PDAI3. Nevertheless, MSC-TPr cross-presented peptides derived from captured soluble proteins. When tested for their protective capacity, MSC-TPr triggered modest anti-tumoral responses despite efficient generation of effector memory CD4 and CD8 T cells. In contrast, clodronate administration prior to vaccination dramatically enhanced the MSC-TPr-induced anti-tumoral immunity clearly highlighting a refractory role mediated by phagocytic cells. Thus, our data elute to a DC cross-priming-dependant pathway in mediating the therapeutic effect of MSC-TPr.

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Mesenchymal Stromal Cells Disrupt mTOR-Signaling and Aerobic Glycolysis During T-Cell Activation

Stem Cells ◽

10.1002/stem.2234 ◽

2015 ◽

Vol 34 (2) ◽

pp. 516-521 ◽

Cited By ~ 15

Author(s):

Martin Böttcher ◽

Andreas D. Hofmann ◽

Heiko Bruns ◽

Martina Haibach ◽

Romy Loschinski ◽

...

Keyword(s):

T Cell ◽

Mesenchymal Stromal Cells ◽

T Cell Activation ◽

Stromal Cells ◽

Cell Activation ◽

Aerobic Glycolysis ◽

Mtor Signaling

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Faculty Opinions recommendation of Cryopreserved mesenchymal stromal cells display impaired immunosuppressive properties as a result of heat-shock response and impaired interferon-γ licensing.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13398985.14768100 ◽

2011 ◽

Author(s):

John Davies ◽

Simon Bubnic

Keyword(s):

Heat Shock ◽

Mesenchymal Stromal Cells ◽

Heat Shock Response ◽

Stromal Cells ◽

Interferon Γ ◽

Shock Response

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Immunomodulatory effects of different intravenous immunoglobulin preparations in chronic lymphocytic leukemia

Scientific Reports ◽

10.1038/s41598-021-92412-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ana Colado ◽

Esteban Enrique Elías ◽

Valeria Judith Sarapura Martínez ◽

Gregorio Cordini ◽

Pablo Morande ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Chronic Lymphocytic Leukemia ◽

T Cell Activation ◽

Cell Activation ◽

Lymphocytic Leukemia ◽

Immunomodulatory Effects ◽

Immunoglobulin Preparations

AbstractHypogammaglobulinemia is the most frequently observed immune defect in chronic lymphocytic leukemia (CLL). Although CLL patients usually have low serum levels of all isotypes (IgG, IgM and IgA), standard immunoglobulin (Ig) preparations for replacement therapy administrated to these patients contain more than 95% of IgG. Pentaglobin is an Ig preparation of intravenous application (IVIg) enriched with IgM and IgA (IVIgGMA), with the potential benefit to restore the Ig levels of all isotypes. Because IVIg preparations at high doses have well-documented anti-inflammatory and immunomodulatory effects, we aimed to evaluate the capacity of Pentaglobin and a standard IVIg preparation to affect leukemic and T cells from CLL patients. In contrast to standard IVIg, we found that IVIgGMA did not modify T cell activation and had a lower inhibitory effect on T cell proliferation. Regarding the activation of leukemic B cells through BCR, it was similarly reduced by both IVIgGMA and IVIgG. None of these IVIg preparations modified spontaneous apoptosis of T or leukemic B cells. However, the addition of IVIgGMA on in vitro cultures decreased the apoptosis of T cells induced by the BCL-2 inhibitor, venetoclax. Importantly, IVIgGMA did not impair venetoclax-induced apoptosis of leukemic B cells. Overall, our results add new data on the effects of different preparations of IVIg in CLL, and show that the IgM/IgA enriched preparation not only affects relevant mechanisms involved in CLL pathogenesis but also has a particular profile of immunomodulatory effects on T cells that deserves further investigation.

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