**3.7 Molecular and cellular interaction of MSCs with innate and acquired immune cells**

### *3.7.1 MSC interaction with T and B cells*

The antigen-specific immune system allows the development of immunological memory. It comprises of CD4+ T helper and CD8+ cytotoxic T lymphocytes that deliver a customized antigen-specific immune response following antigen processing and presentation by antigen-presenting cells (APCs). T helper cells comprise a subpopulation of cells called Tregs, which are specialized in suppression of T cell-mediated immune response [58]. The innate immune system plays an important role in the activation and subsequent course of adaptive immune response [59]. In addition, MSCs are able to suppress in vitro T-cell proliferation induced by cellular or non-specific mitogenic stimuli through the secretion of various soluble factors that include (transforming growth factor-beta 1) TGF-β, HGF, PGE-2, IDO, HLA-G5, and NO. The effect of these suppressive factors is upregulated by pre-sensitization of MSCs with TNF-α and IFN-γ. It is also known that MSCs polarize T cells toward a regulatory phenotype that serves as an important mechanism by which MSCs dampen inflammation [60, 61]. Tregs comprise a subpopulation of T helper cells, which are specialized in suppression of T cell-mediated immune response and characteristically express the forkhead box P3 (Fox P3) transcription factor. These are two main subsets of Tregs including a population of Fox P3+ natural Tregs which are thymus derived and specific for self-antigen and induced or adaptive Tregs that are derived from mature CD4 + CD35-FoxP3 precursors in the periphery following inflammatory stimuli. The in vitro co-culturing of MSCs with PBMNCs induced the differentiation of CD4+ T cells into CD25 + FoxP3+ expressing regulatory T cells [40, 62]. The possible reason of abovementioned mechanism is due to cell-cell contact of MSCs with helper T cells and secretion of PGE-2 and TGF-β. All together, these studies indicate that MSCs are able to maintain the balance between inflammatory effector T cells and anti-inflammatory Tregs.

B cells are also a major cell type involved in adaptive immune response, known for antigen presentation and antibody production. The balance between the different B-cell subsets has been identified as an important factor for optimal graft outcomes. To support the beneficial effect of B-cell depletion at the time of transplantation to impair T cell-mediated allo-response, the CD8 and CD4 T-cell memory is impaired when the antigen-presenting function of B cells is absent [63]. The exposure of enriched B-cell population to irradiated third party PBMNCs led to an increase in immunoglobulin (Ig) production that was abrogated by the addition of MSCs. There are diverse results among the studies to analyze the effect of MSCs upon exposure of isolated pure B cells [64]. These effects have been shown to be cell-cell contact independent or indirect through inhibition of pDC-induced B-cell maturation. On exposure, MSCs increased the viability of B cells and mediated the arrest of cell cycle at G0/G1 and inhibition of their differentiation into plasma cells and subsequent Ig formation, whereas it was observed that pre-treatment of

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*Mesenchymal Stem Cells Modulate the Immune System in Developing Therapeutic Interventions*

MSCs with IFN-γ was necessary for their suppressive effect on B cells [66]. The activated B cells and memory B-cell subsets when exposed to MSCs were seen to increase their survival and proliferation [65]. The studies carried out by Schu et al. [66] showed that when allogeneic MSCs were injected into rats, a strong humoral response was elicited as compared to injection with syngeneic cells in an immuno-

To support whether the allogeneic MSCs exert a humoral response in the recipient to prove the notion, they performed the experiment in which a rat was injected with allogeneic MSCs; on the other hand, contradictory reports were also published stating after transplantation none of them developed anti-MSC antibodies [66]. These studies indicate some disparity of humoral response directed against the injected MSCs, and possible reasons may be the source of MSCs, number of injected cells and frequency of injections, route of administration, or concurrent immuno-

Natural killer cells or NK cells are a type of cytotoxic lymphocytes critical to the innate immune system, evolve as progenitors in the bone marrow, and circulate as mature cells in the blood. They provide rapid responses to viral-infected cells, acting 3 days after infection, and respond to tumor formation. They play a major role in the mechanisms of rejection of graft and are central to the regulation of cytotoxicity in response to human leukocyte antigen molecule. With increasing trends in therapeutic usage of MSCs for treatment of GvHD, it is important to investigate the underlying effects of interaction of MSC and NK cells. They function in the manner that they get activated and inhibited on cell surface because of receptors transmitting the signal into the cell. Usually, NK cell possesses regulatory functions and can secrete cytokines and chemokines which modulate the host's immune response. IL-12 is the most important pro-inflammatory factor which responds to penetrating pathogens and acts through its high affinity receptors. It is released from accessory cells like monocytes, macrophages, and dendritic cells (DCs). Also, the most important cytokine released by NK cells is IFN-γ which is produced upon stimulation of IL-12. The NK cell-derived IFN-y reinforces the expression of IL-12 and DCs via feedback mechanism. BM-MSCs directly interfere with the proliferation, cytokine production, and in some cases cytotoxicity of NK cells. MSC-NK interactions are complex and largely dependent on the microenvironment and activation status of the NK cells. Mainly, MSCs suppress the production of IL-2, IL-15, and INF-γ but not the cytotoxicity of freshly isolated NK cells. In addition, when activated NK cells come into contact with the MSCs, it interferes with NK-mediated cytotoxicity which is primarily mediated by cell-cell contact and secretion of IDO, PGE-2, TGFβ1, and HLA-G5. Other reports mentioned that when licensed MSCs were exposed to IFN-γ, they are protected from NK-mediated cell killing, potentially due to their upregulated cell surface expression of HLA-I and downregulation of ULBP-3. This alongside an increased production of both IDO and PGE-2 offers multiple mecha-

nisms for dampening NK responsiveness to the MSCs [59, 67, 68].

The potent antigen-presenting cells (APCs) and dendritic cells (DCs) play a pivotal role in initiating immune response. The life span of DCs can be divided into two major phases, an immature stage and a mature stage. These phases can be differentiated further on the basis of molecules expressed (CD80, CD86, OX62, HLA-II, and CD11b/c) on their surface. DCs can be immunostimulatory or immunosuppressive,

*3.7.3 MSC interaction with dendritic cells*

*DOI: http://dx.doi.org/10.5772/intechopen.80772*

competent host.

suppression used.

*3.7.2 MSC interaction with NK cells*

#### *Mesenchymal Stem Cells Modulate the Immune System in Developing Therapeutic Interventions DOI: http://dx.doi.org/10.5772/intechopen.80772*

MSCs with IFN-γ was necessary for their suppressive effect on B cells [66]. The activated B cells and memory B-cell subsets when exposed to MSCs were seen to increase their survival and proliferation [65]. The studies carried out by Schu et al. [66] showed that when allogeneic MSCs were injected into rats, a strong humoral response was elicited as compared to injection with syngeneic cells in an immunocompetent host.

To support whether the allogeneic MSCs exert a humoral response in the recipient to prove the notion, they performed the experiment in which a rat was injected with allogeneic MSCs; on the other hand, contradictory reports were also published stating after transplantation none of them developed anti-MSC antibodies [66]. These studies indicate some disparity of humoral response directed against the injected MSCs, and possible reasons may be the source of MSCs, number of injected cells and frequency of injections, route of administration, or concurrent immunosuppression used.
