research article

Mesenchymal Stem Cell-Mediated T Cell Immunosuppression

SatarJabbarRahiAlgraittee1,2,Hamza Lawal1,3, Rajesh Ramasamy1* 

1Stem Cell & Immunity Research Group, Immunology Laboratory, Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia

2Department of Medical Microbiology, College of Medicine, University of Kerbala, Iraq

3Department of Biochemistry, Faculty of Sciences, Bauchi State University, Gadau, itas-Gadau LGA, Nigeria

*Correspondingauthor:Rajesh Ramasamy,Department ofPathology Faculty of Medicine and Health Sciences University Putra Malasiya 43400 UPM Serdang, Selangor,Malaysia. Tel +60389472377; Fax +6038942787; Email: rajesh@upm.edu.my

Received Date:01November, 2017; Accepted Date:21 November, 2017; Published Date:27 November, 2017

Citation:Algraittee SJR, Lawal H, RamasamyR (2017) Mesenchymal Stem Cell-Mediated T Cell Immunosuppression.Stem Cell Res Ther: SCRT-119.DOI: 10.29011/SCRT-119. 000019

1.      Abstract

Besides being a pool forstromal cells and connective tissues, the mesenchymal stem cells (MSCs) as well exert a potent immunosuppression against almost all types of immune cells, particularly T cells. Many in vitro and in vivo studies revealed that the reported regenerative property of MSCs is partially due to the immunosuppressive activity of MSCs where it creates an optimal microenvironment for the execution of reparative and restorative processes. To date, MSCs caninteract with nearly all cells of the immune system, in a convoluted mechanism with theabilityof inhibiting the activation, proliferation, and function of T cells. These characteristicsshowcaseMSCs’ candidature as anaturalimmunosuppressive agent in regenerative medicine,therapies for immune disorders and tissue engineering. In this review, the intricate mechanisms of MSC-mediated immunosuppression on Tcellswere briefly evaluated. The physical, paracrine and molecular interactions that being toolsfor delivering the immunosuppressionwere also highlighted. 

1.      Introduction

Mesenchymal stem cells or stromal cells (MSCs) are classically known as a group of theheterogeneous stromal cell populations with non-hematopoietic natureand, able differentiate into cells of connective tissues[1]. Upon an appropriate induction, MSCs are capable of giving rise to adiverserange of mesodermal lineage tissues, including bone, cartilage, adipose tissue, tendon, and muscle[2]. Besides being a reservoir for various mature cells as of any other type of stem cells,  MSCs as well reported to possess a unique immunosuppressive activity which is mainly reflected in the form of anti-inflammatory activities [3].

Based on the immunosuppressive ability, MSCs have been utilised in various clinical applications since the 1990s[4]. Particularly, the laboratory-expanded MSCs were infused to ameliorate acute and chronicgraft-versus-host disease(GVHD) in patients receiving allogeneichematopoietic stem cell transplantation[5]. Subsequently, several clinical reports on the MSC-based treatment of various diseaseswere published, and as such, it has elicited excitement and promising therapeutic interventions for many degenerative and malignant diseases.These properties cumulate and establish MSCs as a widely accepted ideal candidate cell type in regenerative medicine and therapies for immune disorders and tissue engineering[6].

However, thekey to improvementof the clinical application that exploits immunosuppressive function of MSCs is relying on a better understanding of the upstream and downstream intricatemechanisms. Most of the studies on investigating the immunosuppressive properties of MSCs had extensively focused on unravelling themolecular pathways geared towards exploringand modifying intermediate and cell signalling molecules[7]. This to improve the immunosuppressive characteristics of MSCs and resolve the immunosuppression versus immunogenicity issues raised by previous studies.Thus, in line with the current trend in this field, this review discusses the recent findings on the various mechanisms employed by MSCs, to suppress T cell-mediated immune response. 

2.      Immunosuppressive Properties of MSCs 

In recent years, much attention has been given to the immunosuppressive property of MSCs. Although the exact mechanism that governs such immunosuppressive activity is still elusive, yet the outcome of MSCs treatment in numerous one-off clinical applications and clinical trials had shown a promising therapeutic benefit. Accordingly, Yanez et al. in 2006 showed that adipose tissue-derived MSCs could efficiently control the GvHD associated with allogeneic hematopoietic transplantation[8].The observed immunosuppressive phenomenon is resultant ofvery intricate process where it involves the secretion of immunosuppressive molecules and various growth factors by MSCs[1]. Also, several studies have correlated these immunosuppressive molecules and growth factors with immune homeostasis, reparative and regenerative functions of MSCs[9,10]. 

To start with a simple approach, the secretion of soluble factors and cell-to-cell contact are always the first level in the immunosuppressive cascade where the interaction of target immune cells with MSCs is initiated [11]. This interaction plays a vital part in determining the magnitude of immunosuppression. Although MSCs are known inherently immunosuppressive, in which the ability of MSCs to exert an immunosuppression isindependentof activation triggered by primed T cells, however, some studies support the prerequisite of inflammation to ‘licence’ MSCs. The early work from Djouad et al.suggested that the immunosuppression mediated by MSCs was in response to inflammation as evidenced by the existence of TNF-α, IL-1α/β and IFN-γ[12]. Thus, in response to the inflammatory environment, many soluble factors, as well as immunosuppressive factors along with several chemokine and adhesion molecules, are produced by MSCs. These includeinterleukin (IL)-10, transforming growth factor (TGF)-β and IL-1 receptor antagonist (IL-1Ra), CXCR3 ligands, CCR5 ligands, intercellular adhesion molecule-1(ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). The accumulation of these factors creates a suitable milieu where their concerted effect congregate withan amplified immunosuppression[13]. However, the ability of MSC’s culture supernatant to substantially inhibit the proliferation of T cells indicate a certain degree of theinherent potential of MSCs to exert immunosuppression via soluble factors but enhanced with the existence of inflammation [14]. 

3.  Mechanisms of T Cell Immunosuppression by MSCs 

The MSC-mediated immunosuppression is facilitated by a convoluted mesh of interaction between target immune cells and MSCs through physical contact and secretion of soluble factors. Researchers have suggestedthat the end product of these interactions is the prevention of T-cell activation and inhibition of T cell proliferation leading to direct and indirectimmunosuppression of Tcells[15].Nonetheless, the immunosuppression exerted by MSCs could be dependent on T cells activation where the byproducts of T cells activation needed to prime MSCs to be immunosuppressive. In other words, MSCs support the survival of quiescence T cell and only exert inhibition of proliferation when they are activated[16]. Upon co-culture with MSCs, the cell surface markers of T cell activation like CD25 [17], CD28 [18] and CD69 [19]are downregulated and as a result, the likelihood of antigenic activation of T cells by DCs and other APCs is greatly reduced. This leaves the T-cell population at the naïve orquiescent state [20]. 

Although the mechanisms of Tcell suppression by MSCs can be studied closely by grouping them into two broad groups, i.e. the direct and the indirect mechanism, it is of utmost importance to carefully peruse the factors associated with these mechanisms at the molecular level. 

4.      Indirect Mechanism 

The indirect mechanism of immunosuppression is one of the methods bywhichMSCs escape from immune response and modulate Tcell proliferation. This achieved throughparacrine interactions with other immune cells involving soluble factors, growth factors, growth inhibitors, chemoattractant as well as degradative enzymes. As a result, the normal metabolism and function of immune cells like DCs, Regulatory T Cells (Tregs) and naïve T cells are altered[21]. 

Factors such as PGE2, IL-10,human leukocyte antigen-g5 (HLA-G5), hemeoxygenase1 (HO-1) and transforming growth factor beta (TGF-β) released by MSCs induce the generation and expansion of Tregs which in turn inhibits the proliferation of T cells[21].The endocytosis as well as cell cycle progression from Go to G1of precursors of DCs, CD34+ hematopoieticprogenitorsand monocytes are inhibited by MSCs through IL-6, PGE2, and growth-regulated oncogene-gamma (GRO-γ). In such paracrine manner, the soluble factors secreted by MSCs leads to the impairment of differentiation, maturation, and function of DCs that leads T cell anergy/inactivation. Subsequently, the important cell surface molecules on DCs and the corresponding cytokines such as MHC class II, CD40, CD80, CD83, CD86, IFN-gand IL-12 gets downregulated too. Finally, these impair DC functions by preventingthe formation of afunctional immune synapse with Tcells, antigen presentation ability and hence activation/ proliferation of T cells[21, 22]. 

The functional profile of DCschanges in the presence of MSCs where it induces the generation of tolerogenic DC. One of the potent cytokine secreted by MSCs that able to produce tolerogenic DCs is GRO-γ[22]. Tolerogenic DCs can induce T cell anergy, stimulate Tregs production and Th1 to Th2 phenotype switch. In lymph nodes, MSCs stimulates the downregulation of C-CMotif Chemokine Receptor 7 (CCR-7)on DCs and chemotactic migration to C-C Motif Chemokine Ligand 12 And 19 (CCL-12 and CCL-19)on naïve T- cells. This interaction causes a subside in the migratory property of DCs to regions where naïve T cells are found thereby preventing their activation[23]. 

The effectorfunctions of T and B cells is mainly influenced helper T cells. The cytokines secreted by T helper cells will determine the polarity of immune response either inclines toward the cellular or humoral immunity. Besides the microenvironment, MSCs as well can affect the plasticity and differentiation of helper T cells[24, 25].Upon stimulation, helper T cells are either converted to the proinflammatory Th1 cells (which secrete IFN-g,IL-2 and TNF-α)[26]or the anti-inflammatory Th2 cells (which secretes IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13)[27]. By impairing the generation of specific helper T cells, MSCs could tunedown the cell-mediated immunity and inflammation.Similarly, the Th2 cells are also equally inhibited by MSCs through induction of Tregs[28, 29]. 

5.      Direct Mechanism 

The MSCs mediatedimmunosuppression can be achieved through a direct contact between MSCs and T cells. These interactions involvereceptor-ligand interactions, binding of soluble factors to specific receptors, upregulation and downregulation of the expression of key receptors and ligands. The resultant effect is the direct inhibition of proliferation and prevention of activation of cytotoxic T cells as well as alteration of T helper differentiation [30, 31]. 

In the direct mechanism, the cell-cell contact is an instrument to deliver the required volume of suppression on T cells’ functions. For instance, MSCs bind to T cells through CD200, a protein that expressed on T cell surface which correlates to the downregulation of T cell function[32]. The ligation between programme death ligand 1 (PDL1)  on Tcells binds to its receptor PD1 on MSCs to halt T-cell proliferation[33]. Furthermore, FAS and FASL interactions among these cells trigger the extrinsic pathway of apoptosis[34].To date, approximately 30different soluble factorswere associatedwith mediating immunosuppressive activity of MSCs on T-lymphocyte activation and proliferation[35]. These includesemaphorin-3A[36], hepatic growth factor (HGF)[37], PGE2[38],TGF-β[39],IDO[40], nitric oxide(NO)[41], IL-6[42], IL-10[43], and galectins[44]. These factors bind to specific receptors on T-cells to exert immunosuppressive effects. 

Most of the studies had documented the anti-proliferative effect of MSCs on cell cycle of T cells[11, 45-47]. In acquired immunity, the expansion of antigen-specific T cells is vital, and it permits the amplification of T cell clones once activated to meet the demand of inflammation. Thus, targeting T cell proliferation would be an ideal way to disturb T cell function as a part of immunosuppression. The anti-proliferative activity of MSCs is generic where it halts the expansion of activated T cells by any modes of stimulations. It has been shown that the anti-proliferation is a consequence of cell cycle arrest in which the activated T cells failed to complete the S phase of cell cycle due todetention in G1phase [48]. However, a diverse range of mechanisms had been inflicted to cause this MSC-induced anti-proliferation that affects the signalling pathways of T cell proliferation. 

6.      Conclusion 

Although the utilisationof MSCs to treat tissue degeneration, improve allograft tolerance and curtail inflammation has been shown to be safe and tolerated, yet results from other studies, have reported adverse clinical outcomes that could associate with therapeutic approaches[49]. Hence, thishasprompted the need for a great understanding of the science involved in theinteractions between MSCs and T cells. Despitean enormous amount of data are available,but careful and meticulous scrutiny of the source of MSCs, immunoregulatory mechanisms as well as the response of MSCs to different physiological and biochemical stimuli in both invitroand in vivo environmentis very necessary for the validation of its clinical applications.Although it will be hard to anticipate the mechanisms that mediate MSC-exerted immunosuppression due to many confounding factors such stem cell heterogeneity and variation of in vitro culture, yet identification of such mechanisms is important to delineate the potential adverse effects. Therefore, the exploration of molecular-based studies on the interaction of MSCs and T cells will enable the identification of potential adverse clinical outcome that may arise after MSCs-based therapy as well as the development of therapeutic interventions to address this challenge.



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