Induction of CD4 + CD25 + FOXP3 +  regulatory T cells by mesenchymal stem cells is associated with modulation of ubiquitination factors and TSDR demethylation

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Abstract

Background

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.

Methods

We first investigated the role of cell–cell contact and cytokine secretion by bone marrow-derived MSCs (BM-MSCs) on the induction, stability, and suppressive functions of Tregs under various experimental conditions that lead to Foxp3 generation by flow cytometry and ELISA respectively. Second, we studied the effect of MSCs on TRAF6, GRAIL, USP7, STUB1, and UBC13 mRNA expression in CD4 ⁺ T cells in correlation with the suppressive function of iTregs by real-time PCR; also, we investigated Foxp3 Treg-specific demethylated region (TSDR) methylation in correlation with Foxp3 stability by the high-resolution melting technique. Third, we studied the effect of ex-vivo-expanded BM-MSCs on the induction of transplant tolerance in a model of fully allogeneic skin transplantation. We further analyzed the cytokine secretion patterns in grafted mice as well as the mRNA expression of ubiquitination genes in CD4 ⁺ T cells collected from the spleens of protected mice.

Results

We found that in-vitro MSC-induced Tregs express high mRNA levels of ubiquitination genes such as TRAF6, GRAIL, and USP7 and low levels of STUB1. Moreover, they have enhanced TSDR demethylation. Infusion of MSCs in a murine model of allogeneic skin transplantation prolonged allograft survival. When CD4 ⁺ T cells were harvested from the spleens of grafted mice, we observed that mRNA expression of the Foxp3 gene was elevated. Furthermore, Foxp3 mRNA expression was associated with increased TRAF6, GRAIL, UBC13, and USP7 and decreased STUB1 mRNA levels compared with the levels observed in vitro.

Conclusions

Our data suggest a possible ubiquitination mechanism by which MSCs convert Tconvs to suppressive and stable iTregs.

Electronic supplementary material

The online version of this article (10.1186/s13287-018-0991-1) contains supplementary material, which is available to authorized users.

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Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation.

William Tse, John Pendleton, Wendy Beyer … (2003)

Marrow stromal cells (MSC) can differentiate into multiple mesenchymal tissues. To assess the feasibility of human MSC transplantation, we evaluated the in vitro immunogenicity of MSC and their ability to function as alloantigen presenting cells (APC). Human MSC were derived and used in mixed cell cultures with allogeneic peripheral blood mononuclear cells (PBMC). Expression of immunoregulatory molecules on MSC was analyzed by flow cytometry. An MSC-associated suppressive activity was analyzed using cell-proliferation assays and enzyme-linked immunoassays. MSC failed to elicit a proliferative response when cocultured with allogeneic PBMC, despite provision of a costimulatory signal delivered by an anti-CD28 antibody and pretreatment of MSC with gamma-interferon. MSC express major histocompatibility complex (MHC) class I and lymphocyte function-associated antigen (LFA)-3 antigens constitutively and MHC class II and intercellular adhesion molecule (ICAM)-1 antigens upon gamma-interferon treatment but do not express CD80, CD86, or CD40 costimulatory molecules. MSC actively suppressed proliferation of responder PBMC stimulated by third-party allogeneic PBMC as well as T cells stimulated by anti-CD3 and anti-CD28 antibodies. Separation of MSC and PBMC by a semipermeable membrane did not abrogate the suppression. The suppressive activity could not be accounted for by MSC production of interleukin-10, transforming growth factor-beta1, or prostaglandin E2, nor by tryptophan depletion of the culture medium. Human MSC fail to stimulate allogeneic PBMC or T-cell proliferation in mixed cell cultures. Unlike other nonprofessional APC, this failure of function is not reversed by provision of CD28-mediated costimulation nor gamma-interferon pretreatment. Rather, MSC actively inhibit T-cell proliferation, suggesting that allogeneic MSC transplantation might be accomplished without the need for significant host immunosuppression.

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Regulatory T (Treg) cells play central role in regulation of immune responses to self-antigens, allergens, and commensal microbiota as well as immune responses to infectious agents and tumors. Transcriptional factor Foxp3 serves as a lineage specification factor of Treg cells. Paucity of Treg cells due to loss-of-function mutations of the Foxp3 gene is responsible for highly aggressive, fatal, systemic immune-mediated inflammatory lesions in mice and humans. Recent studies of Foxp3 expression and function provided critical novel insights into biology of Treg cells and into cellular mechanisms of the immune homeostasis. © 2011 John Wiley & Sons A/S.

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Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway.

Silvia Gregori, Daniela Tomasoni, Valentina Pacciani … (2010)

Type 1 T regulatory (Tr1) cells suppress immune responses in vivo and in vitro and play a key role in maintaining tolerance to self- and non-self-antigens. Interleukin-10 (IL-10) is the crucial driving factor for Tr1 cell differentiation, but the molecular mechanisms underlying this induction remain unknown. We identified and characterized a subset of IL-10-producing human dendritic cells (DCs), termed DC-10, which are present in vivo and can be induced in vitro in the presence of IL-10. DC-10 are CD14(+), CD16(+), CD11c(+), CD11b(+), HLA-DR(+), CD83(+), CD1a(-), CD1c(-), express the Ig-like transcripts (ILTs) ILT2, ILT3, ILT4, and HLA-G antigen, display high levels of CD40 and CD86, and up-regulate CD80 after differentiation in vitro. DC-10 isolated from peripheral blood or generated in vitro are potent inducers of antigen-specific IL-10-producing Tr1 cells. Induction of Tr1 cells by DC-10 is IL-10-dependent and requires the ILT4/HLA-G signaling pathway. Our data indicate that DC-10 represents a novel subset of tolerogenic DCs, which secrete high levels of IL-10, express ILT4 and HLA-G, and have the specific function to induce Tr1 cells.

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Author and article information

Contributors

Maryam Khosravi: Maryam3891@yahoo.com

Ali Bidmeshkipour: a.bidmeshkipour@gmail.com

José L. Cohen: jose.cohen@inserm.fr

Ali Moravej: amoravej@gmail.com

Suzzan Hojjat-Assari: s.hojjat.assari@gmail.com

Sina Naserian: sina.naserian@inserm.fr

Mohammad Hossein Karimi: +98 917 3149022 , karimimh@sums.ac.ir

Journal

Journal ID (nlm-ta): Stem Cell Res Ther

Journal ID (iso-abbrev): Stem Cell Res Ther

Title: Stem Cell Research & Therapy

Publisher: BioMed Central (London )

ISSN (Electronic): 1757-6512

Publication date (Electronic): 25 October 2018

Publication date PMC-release: 25 October 2018

Publication date Collection: 2018

Volume: 9

Electronic Location Identifier: 273

Affiliations

[1 ]ISNI 0000 0000 8819 4698, GRID grid.412571.4, Transplant Research Center, , Shiraz University of Medical Sciences, ; Shiraz, Iran

[2 ]ISNI 0000 0000 9149 8553, GRID grid.412668.f, Department of Biology, Faculty of Science, , Razi University, ; Kermanshah, Iran

[3 ]ISNI 0000 0001 2149 7878, GRID grid.410511.0, Université Paris-Est, UMR_S955, UPEC, ; F-94000 Créteil, France

[4 ]ISNI 0000 0004 0386 3258, GRID grid.462410.5, Inserm, U955, ; Equipe 21, F-94000 Créteil, France

[5 ]ISNI 0000 0001 2292 1474, GRID grid.412116.1, UPEC, APHP, Inserm, CIC Biothérapie, , Hôpital Henri Mondor, ; 94010 Créteil, France

[6 ]ISNI 0000 0004 0415 3047, GRID grid.411135.3, Noncommunicable Diseases Research Centre, , Fasa University of Medical Sciences, ; Fasa, Iran

[7 ]Institut Français de Recherche et d’Enseignement Supérieur à l’International (IFRES-INT), Paris, France

[8 ]ISNI 0000 0001 0206 8146, GRID grid.413133.7, Inserm, U1197, , Hôpital Paul Brousse, ; 94807 Villejuif, France

[9 ]SivanCell, Alborz University of Medical Sciences, Alborz, Iran

Article

Publisher ID: 991

DOI: 10.1186/s13287-018-0991-1

PMC ID: 6203284

PubMed ID: 30359308

SO-VID: a3240b4d-cb8d-4f3d-8fef-9574633c503f

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 1 May 2018

Date revision received : 23 August 2018

Date accepted : 23 August 2018

Custom metadata

ScienceOpen disciplines: Molecular medicine

Keywords: mesenchymal stem cells,regulatory t cells,ubiquitination molecules

Data availability:

ScienceOpen disciplines: Molecular medicine

Keywords: mesenchymal stem cells, regulatory t cells, ubiquitination molecules

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