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1.
Stem Cell Res Ther ; 14(1): 229, 2023 08 30.
Article in English | MEDLINE | ID: mdl-37649081

ABSTRACT

BACKGROUND: Native bone marrow (BM) mesenchymal stem/stromal cells (BM-MSCs) participate in generating and shaping the skeleton and BM throughout the lifespan. Moreover, BM-MSCs regulate hematopoiesis by contributing to the hematopoietic stem cell niche in providing critical cytokines, chemokines and extracellular matrix components. However, BM-MSCs contain a heterogeneous cell population that remains ill-defined. Although studies on the taxonomy of native BM-MSCs in mice have just started to emerge, the taxonomy of native human BM-MSCs remains unelucidated. METHODS: By using single-cell RNA sequencing (scRNA-seq), we aimed to define a proper taxonomy for native human BM non-hematopoietic subsets including endothelial cells (ECs) and mural cells (MCs) but with a focal point on MSCs. To this end, transcriptomic scRNA-seq data were generated from 5 distinct BM donors and were analyzed together with other transcriptomic data and with computational biology analyses at different levels to identify, characterize and classify distinct native cell subsets with relevant biomarkers. RESULTS: We could ascribe novel specific biomarkers to ECs, MCs and MSCs. Unlike ECs and MCs, MSCs exhibited an adipogenic transcriptomic pattern while co-expressing genes related to hematopoiesis support and multilineage commitment potential. Furthermore, by a comparative analysis of scRNA-seq of BM cells from humans and mice, we identified core genes conserved in both species. Notably, we identified MARCKS, CXCL12, PDGFRA, and LEPR together with adipogenic factors as archetypal biomarkers of native MSCs within BM. In addition, our data suggest some complex gene nodes regulating critical biological functions of native BM-MSCs together with a preferential commitment toward an adipocyte lineage. CONCLUSIONS: Overall, our taxonomy for native BM non-hematopoietic compartment provides an explicit depiction of gene expression in human ECs, MCs and MSCs at single-cell resolution. This analysis helps enhance our understanding of the phenotype and the complexity of biological functions of native human BM-MSCs.


Subject(s)
Endothelial Cells , Mesenchymal Stem Cells , Humans , Animals , Mice , Bone Marrow Cells , Biomarkers , Sequence Analysis, RNA
2.
Front Immunol ; 12: 717998, 2021.
Article in English | MEDLINE | ID: mdl-34594332

ABSTRACT

Immunoregulatory receptors are essential for orchestrating an immune response as well as appropriate inflammation in infectious and non-communicable diseases. Among them, leukocyte immunoglobulin-like receptors (LILRs) consist of activating and inhibitory receptors that play an important role in regulating immune responses modulating the course of disease progression. On the one hand, inhibitory LILRs constitute a safe-guard system that mitigates the inflammatory response, allowing a prompt return to immune homeostasis. On the other hand, because of their unique capacity to attenuate immune responses, pathogens use inhibitory LILRs to evade immune recognition, thus facilitating their persistence within the host. Conversely, the engagement of activating LILRs triggers immune responses and the production of inflammatory mediators to fight microbes. However, their heightened activation could lead to an exacerbated immune response and persistent inflammation with major consequences on disease outcome and autoimmune disorders. Here, we review the genetic organisation, structure and ligands of LILRs as well as their role in regulating the immune response and inflammation. We also discuss the LILR-based strategies that pathogens use to evade immune responses. A better understanding of the contribution of LILRs to host-pathogen interactions is essential to define appropriate treatments to counteract the severity and/or persistence of pathogens in acute and chronic infectious diseases lacking efficient treatments.


Subject(s)
Communicable Diseases/etiology , Communicable Diseases/metabolism , Disease Susceptibility/immunology , Host-Pathogen Interactions/immunology , Leukocytes/immunology , Leukocytes/metabolism , Receptors, Immunologic/metabolism , Animals , Autoimmunity , Biomarkers , Chromosome Mapping , Communicable Diseases/therapy , Disease Management , Host-Pathogen Interactions/genetics , Humans , Immunity , Immunomodulation , Ligands , Multigene Family , Organ Specificity , Protein Binding , Receptors, Immunologic/genetics
3.
Stem Cells ; 38(6): 782-796, 2020 06.
Article in English | MEDLINE | ID: mdl-32083764

ABSTRACT

Human adipose-derived stem/stromal cells (hASCs) can differentiate into specialized cell types and thereby contribute to tissue regeneration. As such, hASCs have drawn increasing attention in cell therapy and regenerative medicine, not to mention the ease to isolate them from donors. Culture conditions are critical for expanding hASCs while maintaining optimal therapeutic capabilities. Here, we identified a role for transforming growth factor ß1 (TGFß1) in culture medium in influencing the fate of hASCs during in vitro cell expansion. Human ASCs obtained after expansion in standard culture medium (Standard-hASCs) and in endothelial cell growth medium 2 (EGM2-hASCs) were characterized by high-throughput transcriptional studies, gene set enrichment analysis and functional properties. EGM2-hASCs exhibited enhanced multipotency capabilities and an immature phenotype compared with Standard-hASCs. Moreover, the adipogenic potential of EGM2-hASCs was enhanced, including toward beige adipogenesis, compared with Standard-hASCs. In these conditions, TGFß1 acts as a critical factor affecting the immaturity and multipotency of Standard-hASCs, as suggested by small mother of decapentaplegic homolog 3 (SMAD3) nuclear localization and phosphorylation in Standard-hASCs vs EGM2-hASCs. Finally, the typical priming of Standard-hASCs into osteoblast, chondroblast, and vascular smooth muscle cell (VSMC) lineages was counteracted by pharmacological inhibition of the TGFß1 receptor, which allowed retention of SMAD3 into the cytoplasm and a decrease in expression of osteoblast and VSMC lineage markers. Overall, the TGFß1 pathway appears critical in influencing the commitment of hASCs toward osteoblast, chondroblast, and VSMC lineages, thus reducing their adipogenic potential. These effects can be counteracted by using EGM2 culture medium or chemical inhibition of the TGFß1 pathway.


Subject(s)
Adipocytes, Beige/metabolism , Adipocytes, White/metabolism , Adipose Tissue/metabolism , Stromal Cells/metabolism , Transforming Growth Factor beta1/metabolism , Cell Proliferation , Cells, Cultured , Culture Media , Humans
4.
Cell Mol Life Sci ; 76(17): 3323-3348, 2019 Sep.
Article in English | MEDLINE | ID: mdl-31055643

ABSTRACT

Mesenchymal stem cells (MSCs) are isolated from multiple biological tissues-adult bone marrow and adipose tissues and neonatal tissues such as umbilical cord and placenta. In vitro, MSCs show biological features of extensive proliferation ability and multipotency. Moreover, MSCs have trophic, homing/migration and immunosuppression functions that have been demonstrated both in vitro and in vivo. A number of clinical trials are using MSCs for therapeutic interventions in severe degenerative and/or inflammatory diseases, including Crohn's disease and graft-versus-host disease, alone or in combination with other drugs. MSCs are promising for therapeutic applications given the ease in obtaining them, their genetic stability, their poor immunogenicity and their curative properties for tissue repair and immunomodulation. The success of MSC therapy in degenerative and/or inflammatory diseases might depend on the robustness of the biological functions of MSCs, which should be linked to their therapeutic potency. Here, we outline the fundamental and advanced concepts of MSC biological features and underline the biological functions of MSCs in their basic and translational aspects in therapy for degenerative and/or inflammatory diseases.


Subject(s)
Mesenchymal Stem Cells/metabolism , Adipose Tissue/cytology , Bone Marrow Cells/cytology , Cell Differentiation , Cell- and Tissue-Based Therapy , Graft vs Host Disease/prevention & control , Humans , Immunosuppression Therapy , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/cytology , Wnt Signaling Pathway
5.
Stem Cell Res Ther ; 10(1): 56, 2019 02 13.
Article in English | MEDLINE | ID: mdl-30760307

ABSTRACT

Mesenchymal stem/stromal cells (MSCs) delivered as cell therapy to individuals with degenerative and/or inflammatory disorders can help improve organ features and resolve inflammation, as demonstrated in preclinical studies and to some extent in clinical studies. MSCs have trophic, homing/migration, and immunosuppression functions, with many benefits in therapeutics. MSC functions are thought to depend on the paracrine action of soluble factors and/or the expression of membrane-bound molecules, mostly belonging to the molecular class of adhesion molecules, chemokines, enzymes, growth factors, and interleukins. Cutting-edge studies underline bioactive exchanges, including that of ions, nucleic acids, proteins, and organelles transferred from MSCs to stressed cells, thereby improving the cells' survival and function. From this aspect, MSC death modulation function appears as a decisive biological function that could carry a significant part of the therapeutic effects of MSCs. Identifying the function and modes of actions of MSCs in modulating cell death may be exploited to enhance consistency and efficiency of cell therapy that is based on MSCs as medical treatment for degenerative and/or inflammatory diseases. Here, we review the essentials of MSC functions in modulating cell death in unfit cells, and its modes of actions based on current advances and outline the clinical implications.


Subject(s)
Cell- and Tissue-Based Therapy , Inflammation/therapy , Mesenchymal Stem Cell Transplantation/trends , Mesenchymal Stem Cells , Cell Death/genetics , Cell Survival/genetics , Humans , Immunosuppression Therapy/methods , Inflammation/genetics , Inflammation/pathology , Paracrine Communication/genetics
6.
Stem Cells Transl Med ; 6(3): 713-719, 2017 03.
Article in English | MEDLINE | ID: mdl-28297565

ABSTRACT

Mesenchymal stem (stromal) cells (MSCs) are being investigated for treating degenerative and inflammatory disorders because of their reparative and immunomodulatory properties. Intricate mechanisms relate cell death processes with immune responses, which have implications for degenerative and inflammatory conditions. We review the therapeutic value of MSCs in terms of preventing regulated cell death (RCD). When cells identify an insult, specific intracellular pathways are elicited for execution of RCD processes, such as apoptosis, necroptosis, and pyroptosis. To some extent, exacerbated RCD can provoke an intense inflammatory response and vice versa. Emerging studies are focusing on the molecular mechanisms deployed by MSCs to ameliorate the survival, bioenergetics, and functions of unfit immune or nonimmune cells. Given these aspects, and in light of MSC actions in modulating cell death processes, we suggest the use of novel functional in vitro assays to ensure the potency of MSCs for preventing RCD. Such analyses should be associated with existing functional assays measuring the anti-inflammatory capabilities of MSCs in vitro. MSCs selected on the basis of two in vitro functional criteria (i.e., prevention of inflammation and RCD) could possess optimal therapeutic efficacy in vivo. In addition, we underline the implications of these perspectives in clinical studies of MSC therapy, with particular focus on acute respiratory distress syndrome. Stem Cells Translational Medicine 2017;6:713-719.


Subject(s)
Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/cytology , Animals , Biomarkers/metabolism , Cell Death , Humans
7.
Sci Rep ; 6: 26162, 2016 05 19.
Article in English | MEDLINE | ID: mdl-27194621

ABSTRACT

The biological effects of indium-tin-oxide (ITO) are of considerable importance because workers exposed to indium compounds have been diagnosed with interstitial lung disease or pulmonary alveolar proteinosis; however, the pathophysiology of these diseases is undefined. Here, mice intraperitoneally inoculated with ITO-nanoparticles (ITO-NPs) resulted in peritonitis dependent in NLRP3 inflammasome, with neutrophils recruitment and interleukin-1ß (IL-1ß) production. Withal peritoneal macrophages exposed ex vivo to ITO-NPs caused IL-1ß secretion and cytolysis. Further, alveolar macrophages exposed to ITO-NPs in vitro showed ITO-NP endocytosis and production of tumor necrosis factor-α (TNF-α) and IL-1ß, ensued cell death by cytolysis. This cell death was RIPK1-independent but caspase1-dependent, and thus identified as pyroptosis. Endocytosis of ITO-NPs by activated THP-1 cells induced pyroptosis with IL-1ß/TNF-α production and cytolysis, but not in activated THP-1 cells with knockdown of NLRP3, ASC, or caspase1. However, exposing activated THP-1 cells with NLRP3 or ASC knockdown to ITO-NPs resulted in cell death but without cytolysis, with deficiency in IL-1ß/TNF-α, and revealing features of apoptosis. While, mesenchymal stem cells (MSCs) co-cultured with macrophages impaired both inflammation and cell death induced by ITO-NPs. Together, our findings provide crucial insights to the pathophysiology of respiratory diseases caused by ITO particles, and identify MSCs as a potent therapeutic.


Subject(s)
CARD Signaling Adaptor Proteins/metabolism , Caspase 1/metabolism , Macrophages/metabolism , Mesenchymal Stem Cells/physiology , Pyroptosis , Receptors, Cell Surface/metabolism , Tin Compounds/metabolism , Animals , Cells, Cultured , Coculture Techniques , Endocytosis , Humans , Interleukin-1beta/metabolism , Mice , Nanoparticles/administration & dosage , Nanoparticles/metabolism , Neutrophils/immunology , Peritonitis/chemically induced , Tin Compounds/administration & dosage
8.
J Immunol ; 192(4): 1536-46, 2014 Feb 15.
Article in English | MEDLINE | ID: mdl-24453251

ABSTRACT

Inhibition of B cells constitutes a rational approach for treating B cell-mediated disorders. We demonstrate in this article that the engagement of the surface Ig-like transcript 2 (ILT2) inhibitory receptor with its preferential ligand HLA-G is critical to inhibit B cell functions. Indeed, ILT2-HLA-G interaction impedes both naive and memory B cell functions in vitro and in vivo. Particularly, HLA-G inhibits B cell proliferation, differentiation, and Ig secretion in both T cell-dependent and -independent models of B cell activation. HLA-G mediates phenotypic and functional downregulation of CXCR4 and CXCR5 chemokine receptors on germinal center B cells. In-depth analysis of the molecular mechanisms mediated by ILT2-HLA-G interaction showed a G0/G1 cell cycle arrest through dephosphorylation of AKT, GSK-3ß, c-Raf, and Foxo proteins. Crucially, we provide in vivo evidence that HLA-G acts as a negative B cell regulator in modulating B cell Ab secretion in a xenograft mouse model. This B cell regulatory mechanism involving ILT2-HLA-G interaction brings important insight to design future B cell-targeted therapies aimed at reducing inappropriate immune reaction in allotransplantation and autoimmune diseases.


Subject(s)
Antigens, CD/immunology , B-Lymphocytes/immunology , HLA-G Antigens/immunology , Lymphocyte Activation/immunology , Receptors, Immunologic/immunology , Animals , Cell Differentiation/immunology , Cell Movement/immunology , Cell Proliferation , Cells, Cultured , Down-Regulation , Female , Forkhead Transcription Factors/metabolism , G1 Phase Cell Cycle Checkpoints/immunology , Germinal Center/immunology , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Humans , Immunologic Memory/immunology , Leukocyte Immunoglobulin-like Receptor B1 , Mice , Mice, Inbred BALB C , Palatine Tonsil/immunology , Phosphorylation , Protein Binding , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-raf/metabolism , Receptors, CXCR4/biosynthesis , Receptors, CXCR5/biosynthesis , Th2 Cells/immunology , Transplantation, Heterologous
9.
Stem Cells ; 31(11): 2296-303, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23922260

ABSTRACT

Both human leukocyte antigen G (HLA-G) and multipotential mesenchymal stem/stromal cells (MSCs) exhibit immunomodulatory functions. In allogeneic tranplantation, the risks of acute and chronic rejection are still high despite improvement in immunosuppressive treatments, and the induction of a state of tolerance to alloantigens is not achieved. Immunomodulatory properties of MSCs and HLA-G in human allogeneic tranplantation to induce tolerance appears attractive and promising. Interestingly, we and others have demonstrated that MSCs can express HLA-G. In this review, we focus on the expression of HLA-G by MSCs and discuss how to ensure and improve the immunomodulatory properties of MSCs by selectively targeting MSCs expressing HLA-G (MSCs(HLA-G+)). We also discuss the possible uses of MSCs(HLA-G+) for therapeutic purposes, notably, to overcome acute and chronic immune rejection in solid-organ allogeneic transplantation in humans. Since MSCs are phenotypically and functionally heterogeneous, it is of primary interest to have specific markers ensuring that they have strong immunosuppressive potential and HLA-G may be a valuable candidate.


Subject(s)
Biological Therapy/methods , HLA-G Antigens/immunology , Immunosuppression Therapy/methods , Mesenchymal Stem Cells/immunology , Animals , HLA-G Antigens/biosynthesis , Humans , Immunosuppressive Agents/immunology , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/metabolism , Transplantation Immunology , Transplantation, Homologous/methods
10.
FASEB J ; 27(8): 2977-87, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23592762

ABSTRACT

Bone-marrow mesenchymal stem cells (MSCs) are the origin of bone-forming cells with immunomodulation potential. HLA-G5 is among the generated immunosuppressive molecules. HLA-G proteins play a crucial role in promoting the acceptance of allografts. However, the mechanisms regulating the expression of HLA-G5 in human MSCs are unknown. We induced differentiation of MSCs and found that HLA-G5 was greatly up-regulated only in osteoblastic cells (+63% for mRNA). Growth plates and bone callus postfracture in adults showed that only bone-lining cells and mesenchymal progenitors were positive for HLA-G5. Use of gene silencing and dominant-negative factors revealed that HLA-G5 depends on the expression and function of the skeletogenesis master genes RUNX2 and DLX5. In addition, HLA-G5 could directly inhibit osteoclastogenesis by acting on monocytes through SHP1. However, in mature osteoblasts, the expression of HLA-G5 protein was greatly suppressed whereas the proosteoclastogenic factor, RANKL, was concomitantly increased. Down-regulation of HLA-G5 expression during the maturation of osteoblasts was due to binding of the repressor GLI3, a signal transducer of the Hedgehog pathway, to the GLI binding element within the HLA-G promoter. Our findings show that mesenchymal progenitors and osteoblastic cells specifically express HLA-G5 during osteogenesis, with a key role in bone homeostasis.


Subject(s)
Bone and Bones/metabolism , HLA-G Antigens/genetics , Mesenchymal Stem Cells/metabolism , Osteoblasts/metabolism , Osteogenesis/genetics , Adult , Bone and Bones/cytology , Cell Line, Tumor , Cell Lineage/genetics , Cells, Cultured , Core Binding Factor Alpha 1 Subunit/genetics , Core Binding Factor Alpha 1 Subunit/metabolism , Gene Expression Regulation , HLA-G Antigens/metabolism , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Homeostasis/genetics , Humans , Immunohistochemistry , Microscopy, Fluorescence , Models, Genetic , Osteoblasts/cytology , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factors/genetics , Transcription Factors/metabolism
11.
J Immunol ; 183(11): 7054-62, 2009 Dec 01.
Article in English | MEDLINE | ID: mdl-19915057

ABSTRACT

CTLA4-Ig (Belatacept) is a new recombinant molecule that interferes with the signal of T lymphocyte activation and prevents acute rejection after renal transplantation. HLA-G acts as a naturally tolerogenic molecule in humans. In this study, we analyzed whether HLA-G contributes to CTLA4-Ig-mediated graft acceptance. Our results demonstrate that patients treated with CTLA4-Ig displayed significantly higher soluble HLA-G (sHLA-G) plasma concentrations (72 +/- 14 ng/ml) than patients treated with calcineurin inhibitors (5 +/- 1 ng/ml) or healthy donors (5 +/- 5 ng/ml). Notably, sHLA-G purified from plasma of CTLA4-Ig-treated patients was biologically active as it inhibited allogeneic T cell proliferation in vitro. Dendritic cells (DC) were identified as one of the cellular sources of sHLA-G in CTLA4-Ig-treated patients. Supporting this observation, we showed that DC generated in vitro in presence of CTLA4-Ig released sHLA-G in response to allostimulation. These CTLA4-Ig-treated DC acted as tolerogenic APC through sHLA-G secretion as they suppressed T cell alloproliferation, which could be restored by using a neutralizing anti-HLA-G Ab. These data define a novel pathway by which CTLA4-Ig immunomodulates allogenic response through posttranscriptional regulation of HLA-G expression in DC. CTLA4-Ig-mediated HLA-G release appears as a critical factor in T cell alloresponse inhibition, thereby contributing to the immunosuppressive effect and graft acceptance.


Subject(s)
Dendritic Cells/drug effects , Dendritic Cells/immunology , HLA Antigens/metabolism , Histocompatibility Antigens Class I/metabolism , Immunoconjugates/pharmacology , Immunosuppressive Agents/pharmacology , Kidney Transplantation/immunology , Abatacept , Adult , Blotting, Western , Dendritic Cells/metabolism , Enzyme-Linked Immunosorbent Assay , Female , Graft Rejection/immunology , Graft Rejection/prevention & control , HLA Antigens/immunology , HLA-G Antigens , Histocompatibility Antigens Class I/immunology , Humans , Immunohistochemistry , Male , Middle Aged , RNA Processing, Post-Transcriptional , Reverse Transcriptase Polymerase Chain Reaction
12.
Transplantation ; 87(9 Suppl): S62-6, 2009 May 15.
Article in English | MEDLINE | ID: mdl-19424010

ABSTRACT

Adult bone marrow-derived mesenchymal stem cells (MSCs) are multipotential cells capable of regenerating injured tissues. In addition to their multipotency, MSCs inhibit natural killer cell cytotoxicity and T-lymphocyte alloproliferation. Several immunosuppressive mechanisms have been described, including indoleamine 2, 3, -dioxygenase-induced depletion of tryptophan from the lymphocyte environment, and the secretion of prostaglandin E2 and other immunosuppressive factors. Here, we review data supporting a new MSC immunoregulation pathway, in which the key molecule is the human leukocyte antigen-G protein. This nonclassical human leukocyte antigen-class I molecule was initially found on trophoblasts, where it contributes to tolerance at the materno-fetal interface. Because trophoblasts are also able to express indoleamine 2, 3, -dioxygenase and prostaglandin E2, MSC immunomodulatory properties are similar to those of trophoblasts. These mechanisms should be explored in relation to induction of tolerance to alloantigens for the prevention of graft rejection after transplantation.


Subject(s)
HLA Antigens/immunology , Histocompatibility Antigens Class I/immunology , Mesenchymal Stem Cells/immunology , Adult , Bone Marrow Cells/immunology , Bone Marrow Cells/metabolism , Cell Division , Dinoprostone/metabolism , Femur , HLA-G Antigens , Humans , Immunosuppression Therapy , Immunosuppressive Agents/immunology , Lymphocyte Culture Test, Mixed , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Models, Immunological
13.
Stem Cells ; 26(1): 212-22, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17932417

ABSTRACT

Adult bone marrow-derived mesenchymal stem cells (MSCs) are multipotent cells that are the subject of intense investigation in regenerative medicine. In addition, MSCs possess immunomodulatory properties with therapeutic potential to prevent graft-versus-host disease (GvHD) in allogeneic hematopoietic cell transplantation. Indeed, MSCs can inhibit natural killer (NK) function, modulate dendritic cell maturation, and suppress allogeneic T-cell response. Here, we report that the nonclassic human leukocyte antigen (HLA) class I molecule HLA-G is responsible for the immunomodulatory properties of MSCs. Our data show that MSCs secrete the soluble isoform HLA-G5 and that such secretion is interleukin-10-dependent. Moreover, cell contact between MSCs and allostimulated T cells is required to obtain a full HLA-G5 secretion and, as consequence, a full immunomodulation from MSCs. Blocking experiments using neutralizing anti-HLA-G antibody demonstrate that HLA-G5 contributes first to the suppression of allogeneic T-cell proliferation and then to the expansion of CD4(+)CD25(high)FOXP3(+) regulatory T cells. Furthermore, we demonstrate that in addition to their action on the adaptive immune system, MSCs, through HLA-G5, affect innate immunity by inhibiting both NK cell-mediated cytolysis and interferon-gamma secretion. Our results provide evidence that HLA-G5 secreted by MSCs is critical to the suppressive functions of MSCs and should contribute to improving clinical therapeutic trials that use MSCs to prevent GvHD.


Subject(s)
HLA Antigens/metabolism , Histocompatibility Antigens Class I/metabolism , Killer Cells, Natural/metabolism , Mesenchymal Stem Cells/metabolism , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Cytotoxic/metabolism , T-Lymphocytes, Regulatory/metabolism , Adult Stem Cells/cytology , Adult Stem Cells/immunology , Adult Stem Cells/metabolism , Blotting, Western , Bone Marrow Cells/cytology , Bone Marrow Cells/immunology , Bone Marrow Cells/metabolism , CD4 Antigens/metabolism , Cell Communication , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Forkhead Transcription Factors/metabolism , HLA-G Antigens , Humans , Interferon-gamma , Interleukin-10 , Interleukin-2 Receptor alpha Subunit/metabolism , Killer Cells, Natural/immunology , Lymphocyte Culture Test, Mixed , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/immunology , Microscopy, Confocal , Reverse Transcriptase Polymerase Chain Reaction , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Regulatory/immunology
14.
Blood ; 110(12): 3936-48, 2007 Dec 01.
Article in English | MEDLINE | ID: mdl-17804694

ABSTRACT

HLA-G is a tolerogenic molecule whose detection in sera and within allografted tissues is associated with better graft acceptance. HLA-G mediates T-cell differentiation into suppressor cells, which are thought to promote tolerance. Here, we investigated such T cells phenotypically and functionally and assessed their clinical relevance in the peripheral blood of patients who have undergone transplantation. Our results demonstrate that HLA-G expressed by antigen-presenting cells or present as soluble protein down-regulates the expression of CD4 and CD8 on allostimulated T cells at both transcriptional and posttranslational levels. These CD3(+)CD4(low) and CD3(+)CD8(low) T-cell subsets are characterized by an increased proportion of cells expressing CD45RA and HLA-DR, and a decreased number of cells expressing CD62L. In addition, these HLA-G-induced CD3(+)CD4(low) and CD3(+)CD8(low) subpopulations are Foxp3-negative suppressor T cells whose function involves IL-10. Biologic relevance came from analysis of patients who underwent transplantation, with high HLA-G plasma concentrations associated with better graft survival. Peripheral blood from these patients contains increased levels of IL-10 concomitantly to an enhanced representation of CD3(+)CD4(low) and CD3(+)CD8(low) T cells compared with HLA-G-negative patients who underwent transplantation and healthy individuals. These data define novel immunosuppressive subpopulations of peripheral blood T cells induced by HLA-G with potent implications in peripheral tolerance.


Subject(s)
CD3 Complex/immunology , CD4 Antigens/immunology , CD8 Antigens/immunology , CD8-Positive T-Lymphocytes/immunology , Graft Survival/immunology , HLA Antigens/immunology , Histocompatibility Antigens Class I/immunology , Kidney Transplantation/immunology , Liver Transplantation/immunology , Transplantation Tolerance , Adult , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/metabolism , CD3 Complex/biosynthesis , CD4 Antigens/biosynthesis , CD8 Antigens/biosynthesis , CD8-Positive T-Lymphocytes/metabolism , Female , Forkhead Transcription Factors/biosynthesis , Forkhead Transcription Factors/immunology , Gene Expression Regulation/immunology , HLA Antigens/blood , HLA-G Antigens , Histocompatibility Antigens Class I/blood , Humans , Interleukin-10/biosynthesis , Interleukin-10/immunology , L-Selectin/biosynthesis , L-Selectin/immunology , Male , Middle Aged
15.
Transplantation ; 84(1 Suppl): S21-5, 2007 Jul 15.
Article in English | MEDLINE | ID: mdl-17632407

ABSTRACT

Over the past few years, the number of publications concerning the human leukocyte antigen (HLA)-G molecule, its functions, and its pathological implications has greatly increased, largely exceeding those focusing simply on fetal-maternal activity. The role of this molecule in other situations of tolerance such as transplantation, tumor dissemination, or virus infections has also been reported. In this paper, we focus our attention on the relevance of HLA-G in transplantation in the light of recent data associating regulatory T cells and HLA-G, and which provide evidence of the role of HLA-G in improving graft acceptance.


Subject(s)
Cell Transplantation , HLA Antigens/immunology , Immune Tolerance/immunology , Organ Transplantation , Pregnancy/immunology , Transplantation Immunology , Animals , Female , Graft Rejection/immunology , Humans , Transplantation, Homologous/immunology
16.
Hum Immunol ; 68(4): 233-9, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17400057

ABSTRACT

HLA-G is a tolerogenic molecule involved in maternal-fetal tolerance and in allograft acceptance. Soluble HLA-G proteins are present at high levels in plasma from transplanted patients who better accept their graft. In addition, infiltrating mononuclear cells expressing HLA-G can be detected within grafted tissues. To define the role of these HLA-G proteins in preventing graft rejection, we investigated the ability of HLA-G1 expressing antigen presenting cells (APC) and of soluble HLA-G proteins (i.e., HLA-G5 and shed HLA-G1) to inhibit T-cell alloproliferation and analyzed the molecules involved in such inhibition. Results demonstrated that both membrane-bound and soluble HLA-G proteins inhibited T-cell alloproliferation. This inhibition involved engagement of immunoglobulinlike transcript (ILT)-2 and ILT-4 receptors by HLA-G. Moreover, blocking Fas ligand (FasL) reversed HLA-G mediated inhibition, demonstrating that the Fas/FasL pathway is also recruited by HLA-G to exert its immunosuppressive function on T cells. These data highlight the role played by HLA-G in better graft acceptance status observed in transplanted patients with HLA-G(+) grafted cells and high HLA-G plasma levels. Evidence to support such role in vivo was provided by the capacity of purified HLA-G5 from the plasma of the transplanted patient to suppress T-cell alloresponses.


Subject(s)
Antigen-Presenting Cells/immunology , Antigens, CD/physiology , Cell Proliferation , Fas Ligand Protein/physiology , Growth Inhibitors/physiology , HLA Antigens/genetics , Histocompatibility Antigens Class I/genetics , Membrane Glycoproteins/physiology , Receptors, Immunologic/physiology , T-Lymphocytes/immunology , Antigen-Presenting Cells/metabolism , Cell Line, Transformed , Growth Inhibitors/biosynthesis , Growth Inhibitors/genetics , HLA Antigens/biosynthesis , HLA Antigens/physiology , HLA-G Antigens , Histocompatibility Antigens Class I/biosynthesis , Histocompatibility Antigens Class I/physiology , Humans , Leukocyte Immunoglobulin-like Receptor B1 , Membrane Glycoproteins/antagonists & inhibitors , Receptors, Immunologic/antagonists & inhibitors , Signal Transduction/immunology , Solubility , T-Lymphocytes/metabolism
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