Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide

Blood ◽  
2003 ◽  
Vol 101 (9) ◽  
pp. 3722-3729 ◽  
Author(s):  
Mauro Krampera ◽  
Sarah Glennie ◽  
Julian Dyson ◽  
Diane Scott ◽  
Ruthline Laylor ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
Memory T Cells ◽  
T Cell Response ◽  
Target Antigen ◽  
Mhc Molecules

Mesenchymal stem cells (MSCs) have been recently shown to inhibit T-cell proliferation to polyclonal stimuli. We characterized the effect of MSCs of bone marrow origin on the T-cell response of naive and memory T cells to their cognate antigenic epitopes. The immune response to murine male transplantation antigens, HY, was selected because the peptide identity and major histocompatibility complex (MHC) restriction of the immunodominant epitopes are known. C57BL/6 female mice immunized with male cells were the source of memory T cells, whereas C6 mice transgenic for HY-specific T-cell receptor provided naive T cells. Responder cells were stimulated in vitro with male spleen cells or HY peptides in the presence or absence of MSCs. MSCs inhibited HY-specific naive and memory T cells in a dose-dependent fashion and affected cell proliferation, cytotoxicity, and the number of interferon γ (IFN-γ)–producing HY peptide-specific T cells. However, the MSC inhibitory effect did not selectively target antigen-reactive T cells. When MSCs were added to the T-cell cultures in a Transwell system or MSCs were replaced by MSC culture supernatant, the inhibitory activity was abrogated. T-cell reactivity was also restored if MSCs were removed from the cultures. The expression of MHC molecules and the presence in culture of antigen-presenting cells (APCs) or of CD4+/CD25+ regulatory T cells were not required for MSCs to inhibit. We conclude that MSCs inhibit naive and memory T-cell responses to their cognate antigens. Overall our data suggest that MSCs physically hinder T cells from the contact with APCs in a noncognate fashion.

scholarly journals Inhibition of Allogeneic and Autologous T Cell Proliferation by Adipose-Derived Mesenchymal Stem Cells of Ankylosing Spondylitis Patients

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Ewa Kuca-Warnawin ◽  
Magdalena Plebańczyk ◽  
Krzysztof Bonek ◽  
Ewa Kontny
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
Ankylosing Spondylitis ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Response ◽  
T Cell Proliferation

Background. In ankylosing spondylitis (AS), accompanied by chronic inflammation, T cell expansion plays a pathogenic role; the immunoregulatory properties of bone marrow-derived mesenchymal stem cells (BM-MSCs) are impaired, while functional characteristics of their adipose tissue-derived counterparts are (ASCs) unknown. Methods. We evaluated the antiproliferative activity of AS/ASCs, obtained from 20 patients, towards allogeneic and autologous T lymphocytes, using ASCs from healthy donors (HD/ASCs) as the reference cell lines. The PHA-activated peripheral blood mononuclear cells (PBMCs) were cocultured in cell-cell contact and transwell conditions with untreated or TNF + IFNγ- (TI-) licensed ASCs, then analyzed by flow cytometry to identify proliferating and nonproliferating CD4+ and CD8+ T cells. The concentrations of kynurenines, prostaglandin E2 (PGE2), and IL-10 were measured in culture supernatants. Results. In an allogeneic system, HD/ASCs and AS/ASCs similarly decreased the proliferation of CD4+ and CD8+ T cells and acted mainly via soluble factors. The concentrations of kynurenines and PGE2 inversely correlated with T cell proliferation, and selective inhibitors of these factors synthesis significantly restored T cell response. AS/ASCs exerted a similar antiproliferative impact also on autologous T cells. Conclusion. We report for the first time that despite chronic in vivo exposure to inflammatory conditions, AS/ASCs retain the normal capability to restrain expansion of allogeneic and autologous CD4+ and CD8+ T cells, act primarily via kynurenines and PGE2, and thus may have potential therapeutic value. Some distinctions between the antiproliferative effects of AS/ASCs and HD/ASCs suggest in vivo licensing of AS/ASCs.

Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells

Blood ◽  
2006 ◽  
Vol 109 (1) ◽  
pp. 228-234 ◽  
Author(s):  
Kazuya Sato ◽  
Katsutoshi Ozaki ◽  
Iekuni Oh ◽  
Akiko Meguro ◽  
Keiko Hatanaka ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Stem Cells ◽  
Cell Proliferation ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Specific Inhibitor ◽  
T Cell Proliferation

Abstract The molecular mechanisms by which mesenchymal stem cells (MSCs) suppress T-cell proliferation are poorly understood, and whether a soluble factor plays a major role remains controversial. Here we demonstrate that the T-cell–receptor complex is not a target for the suppression, suggesting that downstream signals mediate the suppression. We found that Stat5 phosphorylation in T cells is suppressed in the presence of MSCs and that nitric oxide (NO) is involved in the suppression of Stat5 phosphorylation and T-cell proliferation. The induction of inducible NO synthase (NOS) was readily detected in MSCs but not T cells, and a specific inhibitor of NOS reversed the suppression of Stat5 phosphorylation and T-cell proliferation. This production of NO in the presence of MSCs was mediated by CD4 or CD8 T cells but not by CD19 B cells. Furthermore, inhibitors of prostaglandin synthase or NOS restored the proliferation of T cells, whereas an inhibitor of indoleamine 2,3-dioxygenase and a transforming growth factor–β–neutralizing antibody had no effect. Finally, MSCs from inducible NOS−/− mice had a reduced ability to suppress T-cell proliferation. Taken together, these results suggest that NO produced by MSCs is one of the major mediators of T-cell suppression by MSCs.

scholarly journals Intrinsic Variability Present in Wharton’s Jelly Mesenchymal Stem Cells and T Cell Responses May Impact Cell Therapy

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Fernanda Vieira Paladino ◽  
Luiz Roberto Sardinha ◽  
Carla Azevedo Piccinato ◽  
Anna Carla Goldberg
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
Replicative Senescence ◽  
T Cell Response ◽  
Wharton’S Jelly ◽  
T Cell Proliferation ◽  
Intrinsic Variability ◽  
Wharton's Jelly

Wharton’s jelly mesenchymal stem cells (WJ-MSC) exhibit immunomodulatory effects on T cell response. WJ-MSC are easy to collect, process, and proliferate rapidly in culture, but information on the variability of individual cell samples impacting upon in vitro expansion, immunomodulatory potential, and aging processes is still lacking. We propose to evaluate the immunomodulatory cytokine profile and capacity to inhibit T cell proliferation of WJ-MSC progressing to replicative senescence in order to analyze if expected responses are affected. Our results show that the gene expression of immunomodulatory molecules varied among samples with no specific pattern present. In coculture, all WJ-MSC were capable of inhibiting mitogen-activated CD3+ T cell proliferation, although to different degrees, and each PBMC responded with a different level of inhibition. Thus, we suggest that each WJ-MSC displays unique behavior, differing in patterns of cytokine mRNA expression and immunomodulatory capacity. We believe that variability between samples may play a role in the effectiveness of WJ-MSC employed therapeutically.

Mesenchymal Stem Cells Inhibit Th17 Differentiation through PGE2 Production.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3633-3633
Author(s):  
Raine Tatara ◽  
Katsutoshi Ozaki ◽  
Lekuni Oh ◽  
Keiko Hatanaka ◽  
Akiko Meguro ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Stem Cells ◽  
Cell Proliferation ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
T Cell Proliferation ◽  
Th17 Differentiation ◽  
Treg Differentiation ◽  
Immunomodulatory Function

Abstract Abstract 3633 Poster Board III-569 Mesenchymal stem cells (MSCs) possess an immunomodulatory function and show promise as a cell therapy for graft-versus-host disease (GVHD). In a phase II study in Europe, injections of MSCs caused 60-70% overall response rate, with longer survival of complete responder. In contrast to its clinical efficacy, the molecular mechanism(s) underlying immunomodulation by MSCs has not been fully established. Prostaglandin E2 (PGE2), tumor growth factor-b1 (TGF-b1), and indoleamine-2,3-dioxygenase have been reported to mediate the immunomodulatory function of MSCs, and we reported evidence that nitric oxide is also a mediator (Blood 2007, 109, 228). Th17 is a recently recognized differentiation category, in which CD4 cells produce IL-17. It has been reported that Th17 is crucial for experimental autoimmune encephalomyelitis (a model of the human disease, multiple sclerosis) and is also thought to be important in other autoimmune diseases. Regulatory T cells (Treg) are another newly recognized differentiation category, in which CD4 T cells have high levels of Foxp3 expression and suppress T cell proliferation. It has been reported that Th17 and Treg can be induced by incubation with TGF-b1 and IL-6 or IL-21, and TGF-b1 and IL-2, respectively, and that these two differentiations are in a reciprocal relationship. Whereas the role of Th17 in GVHD is still controversial, Treg has been reported to suppress GVHD in a mouse model. To elucidate the molecular mechanism(s) of the immunomodulatory function of MSCs, we herein sought to identify the effects of MSCs on these relatively new differentiations. MSCs inhibit Th17 differentiation even in conditions in which growth is not completely inhibited. Interestingly, an inhibitor of prostaglandin production, indomethacin, and an inhibitor of indoleamine 2,3-dioxygenase, 1-methyltryptophan, partially restore Th17 differentiation, whereas inhibitors of nitric oxide synthase do not. These results suggest that PGE2 and depletion of tryptophan, but not nitric oxide, mediate inhibitory effects of MSCs on Th17. Additionally, we found that MSCs produced PGE2 when co-cultured with CD4 T cells in Th17 differentiation condition and PGE2 per se suppresses Th17 differentiation. Thus, our results suggest that MSCs block Th17 differentiation through PGE2 prodction. In contrast to Th17 differentiation, Treg differentiation was not significantly inhibited by MSCs. However, MSCs still inhibited proliferation of T cells under these conditions, and T cell proliferation was restored by the addition of indomethacin. These results suggest that MSCs inhibit proliferation but not Treg differentiation through PGE2 production. The mechanism by which PGE2 differentially regulates these differentiations is unknown and remains an area for further investigation. Disclosures: Ozawa: Alexion: Research Funding.

Dose and Timing Limitations in the Use of Bone Marrow-Derived Mesenchymal Stem Cells for the Treatment of Experimental Arthritis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2326-2326
Author(s):  
Evangelia Yannaki ◽  
Anastasia Papadopoulou ◽  
Minas Yiangou ◽  
Evangelia Athanasiou ◽  
Argyrw Paraskeva ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
Broad Spectrum ◽  
Synovial Membrane ◽  
Cell Contact ◽  
Dependent Manner

Abstract The recently recognized potential of mesenchymal stem cells (MSCs) to differentiate into a broad spectrum of tissues and to act as immune regulators beyond the barriers of embryonic germ layers and major histocombatibility comlex (MHC) restriction, has emerged intense research interest on their possible use in a broad spectrum of clinical entities. Although the immunoregulatory potential of MSCs has been shown to effectively control GvHD in several preclinical and clinical studies, their role in autoimmune diseases has not been extensively explored in animal models. The goal of this study was to investigate the in vitro effect of rat bone marrow-derived MSCs on cultured fibrobIast-like synoviocytes (FLS) and T-cells from the spleen after induction of adjuvant arthritis (AA) by FCA as well as their in vivo effect in a rat model of AA resembling human rheumatoid arthritis. MSCs were isolated from bone marrow and were characterized by CD45 negativity and CD54, CD29 positivity in FCM analysis. Differentiation assays were performed to confirm their adipogenic, osteogenic and chondrogenic potential. Culture of AA-FLS in the presence of supernatant from syngeneic (syng) or allogeneic (allo) MSCs at passage 2–3, reduced the AA-FLS (p<0.022) and the ConA-stimulated AA-T-cell (p=0.04) proliferation in a dose-dependent manner, as compared to AA-FLS or AA-T-cell proliferation in the absence of supernatant. Cell-to-cell contact by coculture of activated T-cells with syng or allo MSCs produced a stronger inhibition over the supernatant (p<0.0001), in all tested MSCs dilutions and even at the lowest MSCs :T-cell ratio of 0.05:1. The inhibitory effect of allo as compared to syng MSCs in activated AA T-cells, was stronger both by secreted agents (p=0.017) or by cell to cell contact (p=0.0001). In vivo, low doses of syng MSCs (0.5-5x10^5cell/recipient) administered iv, intrasplenic or intrabone marrow, at single or multiple infusions, didn’t significantly reduce the disease score of MSC-treated as compared to control rats. In contrast, repeated, higher dose (6x10^6cell/recipient), iv infusions of syng or allogeneic MSCs from male donors (Y+MSCs) to female recipients, before the onset of AA (d4 and d9 post AA induction) resulted in significantly lower arthritic scores when compared to control animals. MSC-treated animals preserved a rather normal joint architecture with focal synovial hyperplasia, limited pannus formation and without bone destruction or chondroplasia. In contrast, the joints of arthritic control rats, appeared with a thickened synovial membrane, erosive pannus and dense inflammatory cell infiltration, chondroplasia and osteoplasia. Reduced presence of CD3+, CD11b+, NF-kb+ cells and less intense angiogenesis (FVIII+cells) was demonstrated by immunohistochemistry in the synovium of transplanted rats as compared to the control group. No Y+MSCs were detected in the spleen, bone marrow or in cultured FLS from the synovial membrane at day30 post AA induction, by PCR (sry gene), immunohistochemistry (sry protein) or FISH (Y chromosome), suggesting that the observed benefit was mostly a result of immunomodulation not derived by MSCs homing to target tissues, or migration of MSCs to target tissues may have occured earlier. On the other hand, when the same cell dose was injected after the onset of arthritis (d13 and d20 post AA induction) no clinical benefit could be observed. Our data suggest that MSCs may represent a new therapeutic approach for autoimmune arthritis, however, due to dose and timing limitations in their use, further studies are needed to clinically exploit this potential.

Enhancement of T Cell Development in Murine Bone Marrow Transplant Recipients by Transfer of the IL-7 or SCF Gene into Marrow-Derived Mesenchymal Stem Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3572-3572
Author(s):  
Brile Chung ◽  
Dullei Min ◽  
Mark Krampf ◽  
Won Jong Ju ◽  
Kenneth I. Weinberg
Keyword(s):  
Stem Cells ◽  
Gene Therapy ◽  
Bone Marrow ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
Immune Reconstitution ◽  
T Cell Development ◽  
Cell Development ◽  
Allogeneic Bmt

Abstract The ability of the thymus to generate T cells diminishes with increasing age, the use of chemotherapy, bone marrow transplantation (BMT), anti-retroviral therapy for HIV, and graft-versus-host disease (GVHD) which can lead to a major clinical problem. Therefore, developing a clinically relevant strategy for the rapid development of T lymphocytes is crucial for treating immune deficiency. Stem cell factor (SCF: also known as kit ligand) and interleukin-7 (IL-7) are stroma–derived cytokines that induce proliferation, differentiation, and survival of developing immature T cells in the thymus. Studies have shown that administration of recombinant human IL-7 following murine BMT resulted in improved thymopoiesis and immune function. However, our previous studies have shown that that IL-7 treatment post-HSCT to enhance immune reconstitution in the allogeneic setting may have adverse effects because of the dual role of IL-7 in supporting both thymopoiesis and mature T lymphocyte expansion. Therefore it raises the question of whether IL-7 treatment after allogeneic BMT will increase the frequency or severity of GVHD. The purpose of this study was to examine whether: administration of IL-7 and SCF with infusion of mature T cell depleted (TCD) BM cells can induce enhancement of donor-derived immune reconstitution more rapidly than treatment with either cytokine alone and whether IL-7 and SCF are synergistic and partially complementary signals for the proliferation, survival, and differentiation of immature T cells. To evaluate the combinatory effect of IL-7 and SCF in T cell development following BMT, we developed a gene therapy approach using retrovirally-mediated transduction of BM-derived mesenchymal stem cells (MSC) with the human IL-7 or murine SCF gene (soluble isoform). C57BL/6J (CD45.2) recipient mice were irradiated (1300 cGy) and co-transplanted with 1 × 10 6 T cell depleted (TCD) bone marrow cells from congenic donor B6.SJL mice (CD45.1) and different doses (0.1 × 10 6 or 0.3 × 10 6) of eGFP (control), IL-7, SCF, or combination of IL-7 and SCF MSC. At day 30 following BMT, we observed that transplantation of both IL-7 and SCF MSC resulted in significantly higher numbers of donor-derived thymocytes and peripheral lymphocytes than either IL-7 or SCF MSC transplantation alone. Most noticeably, the number of donor-derived immature and mature T cells recovered from the animals receiving transplantation of 0.1 × 10 6 IL-7 MSC and 0.3 × 10 6 SCF MSC was similar to that of animals receiving 0.3 × 10 6 IL-7 MSC alone, demonstrating that the reduced proliferative signals produced by 0.1 × 10 6 IL-7 MSC can be compensated by co-transplantation of 0.3 × 10 6 SCF MSC. Moreover, transplantation of IL-7 and SCF MSC significantly increased the number of donor-derived common lymphoid progenitors (CLP [Lin-, Sca-1 low, Thy1-, c-Kit low, IL-7R+]) in the BM, suggesting that transplanted CLPs are induced to differentiate or expand more rapidly in response to IL-7 and SCF and may have contributed to increased immune reconstitution. Collectively, our findings demonstrate that IL-7 and SCF gene therapy may be a therapeutically useful method to promote enhancement of T cell development in de novo. Furthermore, the experiments resulted in important knowledge about complementary signals provided between IL-7 and SCF, and suggest various doses of IL-7 and SCF therapy may enhance development of T cells with limited expansion of mature T cells responsible for causing GVHD in allogeneic BMT setting.

scholarly journals IL7-IL12 Engineered Mesenchymal Stem Cells (MSCs) Improve A CAR T Cell Attack Against Colorectal Cancer Cells

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 873 ◽  
Author(s):  
Andreas A. Hombach ◽  
Ulf Geumann ◽  
Christine Günther ◽  
Felix G. Hermann ◽  
Hinrich Abken
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
Tumor Model ◽  
T Cell Response ◽  
Car T Cells ◽  
Car T Cell ◽  
Activation Induced Cell Death ◽  
Car T

Chimeric antigen receptor (CAR) redirected T cells are efficacious in the treatment of leukemia/lymphoma, however, showed less capacities in eliminating solid tumors which is thought to be partly due to the lack of cytokine support in the tumor lesion. In order to deliver supportive cytokines, we took advantage of the inherent ability of mesenchymal stem cells (MSCs) to actively migrate to tumor sites and engineered MSCs to release both IL7 and IL12 to promote homeostatic expansion and Th1 polarization. There is a mutual interaction between engineered MSCs and CAR T cells; in presence of CAR T cell released IFN-γ and TNF-α, chronic inflammatory Th2 MSCs shifted towards a Th17/Th1 pattern with IL2 and IL15 release that mutually activated CAR T cells with extended persistence, amplification, killing and protection from activation induced cell death. MSCs releasing IL7 and IL12 were superior over non-modified MSCs in supporting the CAR T cell response and improved the anti-tumor attack in a transplant tumor model. Data demonstrate the first use of genetically modified MSCs as vehicles to deliver immuno-modulatory proteins to the tumor tissue in order to improve the efficacy of CAR T cells in the treatment of solid malignancies.

The immunosuppressive effects of human bone marrow-derived mesenchymal stem cells target T cell proliferation but not its effector function

2008 ◽  
Vol 251 (2) ◽  
pp. 131-136 ◽  
Author(s):  
Rajesh Ramasamy ◽  
Chih Kong Tong ◽  
Heng Fong Seow ◽  
Sharmili Vidyadaran ◽  
Francesco Dazzi
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
Effector Function ◽  
Human Bone ◽  
Human Bone Marrow ◽  
T Cell Proliferation
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