T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression

AbstractInfusion of either embryonic or mesenchymal stem cells prolongs the survival of organ transplants derived from stem cell donors and prevents graft-versus-host-disease (GVHD). An in-depth mechanistic understanding of this tolerization phenomenon could lead to novel cell-based therapies for transplantation. Here we demonstrate that while human mesenchymal stem cells (hMSCs) can promote superantigen-induced activation of purified T cells, addition of antigen-presenting cells (APCs; either monocytes or dendritic cells) to the cultures inhibits the T-cell responses. This contact- and dose-dependent inhibition is accompanied by secretion of large quantities of interleukin (IL)–10 and aberrant APC maturation, which can be partially overridden by the addition of factors that promote APC maturation (ie, lipopolysaccharide [LPS] or anti-CD40 monoclonal antibody [mAb]). Thus, our data support an immunoregulatory mechanism wherein hMSCs inhibit T cells indirectly by contact-dependent induction of regulatory APCs with T-cell–suppressive properties. Our data may reveal a physiologic phenomenon whereby the development of a distinct APC population is regulated by the tissue's cellular microenvironment.

Download Full-text

Human adipose-derived mesenchymal stem cells reduce inflammatory and T cell responses and induce regulatory T cells in vitro in rheumatoid arthritis

Annals of the Rheumatic Diseases ◽

10.1136/ard.2008.101881 ◽

2009 ◽

Vol 69 (01) ◽

pp. 241-248 ◽

Cited By ~ 244

Author(s):

E Gonzalez-Rey ◽

M A Gonzalez ◽

N Varela ◽

F O’Valle ◽

P Hernandez-Cortes ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Stem Cells ◽

T Cells ◽

Mesenchymal Stem Cells ◽

T Cell ◽

Regulatory T Cells ◽

Inflammatory Responses ◽

T Cell Responses ◽

Cell Responses ◽

Adult Mesenchymal Stem Cells

Objectives:Adult mesenchymal stem cells were recently found to suppress effector T cell and inflammatory responses and have emerged as attractive therapeutic candidates for immune disorders. In rheumatoid arthritis (RA), a loss in the immunological self-tolerance causes the activation of autoreactive T cells against joint components and subsequent chronic inflammation. The aim of this study is to characterise the immunosuppressive activity of human adipose-derived mesenchymal stem cells (hASCs) on collagen-reactive T cells from patients with RA.Methods:The effects of hASCs on collagen-reactive RA human T cell proliferation and cytokine production were investigated, as well as effects on the production of inflammatory mediators by monocytes and fibroblast-like synoviocytes from patients with RA.Results:hASCs suppressed the antigen-specific response of T cells from patients with RA. hASCs inhibited the proliferative response and the production of inflammatory cytokines by collagen-activated CD4 and CD8 T cells. In contrast, the numbers of IL10-producing T cells and monocytes were significantly augmented upon hASC treatment. The suppressive activity of hASCs was cell-to-cell contact dependent and independent. hASCs also stimulated the generation of FoxP3 protein-expressing CD4+CD25+ regulatory T cells, with the capacity to suppress collagen-specific T cell responses. Finally, hASCs downregulated the inflammatory response and the production of matrix-degrading enzymes by synovial cells isolated from patients with RA.Conclusions:The present work identifies hASCs as key regulators of immune tolerance, with the capacity to suppress T cell and inflammatory responses and to induce the generation/activation of antigen-specific regulatory T cells.

Download Full-text

Mesenchymal stem cells improve renal injury in diabetic rats by inhibiting CD103 + DCs maturation to decline CD8 + T cell responses

The FASEB Journal ◽

10.1096/fasebj.2019.33.1_supplement.662.24 ◽

2019 ◽

Vol 33 (S1) ◽

Author(s):

Fuping Zhang ◽

Chengshi Wang ◽

Ruiwen Mao ◽

Younan Chen ◽

Jingqiu Cheng ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

T Cell ◽

Renal Injury ◽

T Cell Responses ◽

Cd8 T Cell ◽

Diabetic Rats ◽

Cell Responses

Download Full-text

Mesenchymal stem cells alleviate rat diabetic nephropathy by suppressing CD103 + DCs‐mediated CD8 + T cell responses

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.15250 ◽

2020 ◽

Vol 24 (10) ◽

pp. 5817-5831

Author(s):

Fuping Zhang ◽

Chengshi Wang ◽

Xin Wen ◽

Yang Chen ◽

Ruiwen Mao ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Diabetic Nephropathy ◽

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Responses

Download Full-text

Mesenchymal stem cells exert differential effects on alloantigen and virus-specific T-cell responses

Blood ◽

10.1182/blood-2007-10-119370 ◽

2008 ◽

Vol 112 (3) ◽

pp. 532-541 ◽

Cited By ~ 113

Author(s):

Helen Karlsson ◽

Sujith Samarasinghe ◽

Lynne M. Ball ◽

Berit Sundberg ◽

Arjan C. Lankester ◽

...

Keyword(s):

Stem Cells ◽

T Cells ◽

Mesenchymal Stem Cells ◽

T Cell ◽

Mononuclear Cells ◽

T Cell Responses ◽

Third Party ◽

Cell Functions ◽

Cell Responses ◽

Ifn Γ

Abstract Mesenchymal stem cells (MSCs) suppress alloantigen-induced T-cell functions in vitro and infusion of third-party MSCs seems to be a promising therapy for graft-versus-host disease (GVHD). Little is known about the specificity of immunosuppression by MSCs, in particular the effect on immunity to pathogens. We have studied how MSCs affect T-cell responses specific to Epstein-Barr virus (EBV) and cytomegalovirus (CMV). We found that EBV- and CMV-induced proliferation and interferon-γ (IFN-γ) production from peripheral blood mononuclear cells (PBMCs) was less affected by third-party MSCs than the response to alloantigen and that MSCs had no effect on expansion of EBV and CMV pentamer-specific T cells. Established EBV-specific cytotoxic T cells (CTL) or CMV-CTL cultured with MSCs retained the ability to proliferate and produce IFN-γ in response to their cognate antigen and to kill virally infected targets. Finally, PBMCs from 2 patients who received MSCs for acute GVHD showed persistence of CMV-specific T cells and retained IFN-γ response to CMV after MSC infusion. In summary, MSCs have little effect on T-cell responses to EBV and CMV, which contrasts to their strong immunosuppressive effects on alloreactive T cells. These data have major implications for immunotherapy of GVHD with MSCs and suggest that the effector functions of virus-specific T cells may be retained after MSC infusion.

Download Full-text

Myeloid-Derived Suppressor Cells Accumulate in Intestinal Transplant Patients and Suppress Anti-Donor T-Cell Responses to Donor Epithelial Stem Cells

Transplantation Journal ◽

10.1097/01.tp.0000521425.21487.8d ◽

2017 ◽

Vol 101 ◽

pp. S95

Author(s):

Shinji Okano ◽

Kareem Abu-Elmagd ◽

Robert L. Fairchild ◽

Masato Fujiki ◽

Ajai Khanna ◽

...

Keyword(s):

Stem Cells ◽

T Cell ◽

Suppressor Cells ◽

T Cell Responses ◽

Myeloid Derived Suppressor Cells ◽

Epithelial Stem Cells ◽

Cell Responses ◽

Transplant Patients ◽

Intestinal Transplant

Download Full-text

Transcriptome Profiling of IL-17A Preactivated Mesenchymal Stem Cells: A Comparative Study to Unmodified and IFN-γModified Mesenchymal Stem Cells

Stem Cells International ◽

10.1155/2017/1025820 ◽

2017 ◽

Vol 2017 ◽

pp. 1-16 ◽

Cited By ~ 10

Author(s):

Kisha Nandini Sivanathan ◽

Darling Rojas-Canales ◽

Shane T. Grey ◽

Stan Gronthos ◽

Patrick T. Coates

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

T Cell ◽

Antigen Processing ◽

Cellular Therapy ◽

Human Mesenchymal Stem Cells ◽

Humoral Response ◽

Transcriptome Profiling ◽

Antigen Processing And Presentation ◽

Immunomodulatory Function

Human mesenchymal stem cells pretreatment with IL-17A (MSC-17) potently enhances T cell immunosuppression but not their immunogenicity, in addition to avidly promoting the induction of suppressive regulatory T cells. The aim of this study was to identify potential mechanisms by which human MSC-17 mediate their superior immunomodulatory function. Untreated-MSC (UT-MSC), IFN-γtreated MSC (MSC-γ), and MSC-17 were assessed for their gene expression profile by microarray. Significantly regulated genes were identified for their biological functions (Database for Annotation, Visualisation and Integrated Discovery, DAVID). Microarray analyses identified 1278 differentially regulated genes between MSC-γand UT-MSC and 67 genes between MSC-17 and UT-MSC. MSC-γwere enriched for genes involved in immune response, antigen processing and presentation, humoral response, and complement activation, consistent with increased MSC-γimmunogenicity. MSC-17 genes were associated with chemotaxis response, which may be involved in T cell recruitment for MSC-17 immunosuppression. MMP1, MMP13, and CXCL6 were highly and specifically expressed in MSC-17, which was further validated by real-time PCR. Thus, MMPs and chemokines may play a key role in mediating MSC-17 superior immunomodulatory function. MSC-17 represent a potential cellular therapy to suppress immunological T cell responses mediated by expression of an array of immunoregulatory molecules.

Download Full-text