• Patients' bone marrow-derived MSCs induce T lymphocytes differentiation into Treg
  • Batol Abbasi,1,*
    1. Tabriz University of Medical Sciences


  • Introduction: Abstract The escape of cancer cells from the immune system is one of the factors that contribute to the spread of neoplastic cells in various forms of cancer. Regulatory T cells (Tregs) play an important role in modulating or suppressing the immune system. Patients with leukemia have an increased number of Treg cells in their peripheral blood (PB) and bone marrow (BM) compared to healthy individuals. Meanwhile, previous studies have shown that mesenchymal stem cells (MSCs) increase the differentiation of Treg cells from CD4+ T cells. Therefore, in this article, we review the effect of MSC on increasing the frequency of Treg cells and immunosuppression in cancer patients.
  • Methods: Introduction Regulatory T cells (Tregs) are a subpopulation of CD4+ T lymphocytes that play an important role in the induction of peripheral tolerance to self and foreign antigens and suppress the immune response (1–3). Tregs are divided into two categories based on the place of distinction. Induced Treg (iTreg) are cells produced in peripheral lymphatic organs as a result of the detection of a local antigen outside the thymus, whereas normal Treg (nTreg) form within the thymus upon maturation. Both cell populations express FOXP3+ CD4+ CD25+ markers, and their suppressive activity is essential for establishing and maintaining stable immune homeostasis (3,4). Tregs can promote tumor development and progression by hindering the effector immune response (5–7). Tregs use multiple mechanisms to suppress the immune system: 1) signaling inhibition of CD80 and CD86 costimulatory molecules on dendritic cells (DC) via cytotoxic T lymphocyte 4 antigen (CTLA4), 2) secretion of inhibitory cytokines, 3) interleukin‐2 (IL-2) utilization through high CD25 (IL‐2 receptor α‐chain) expression, 4) metabolic modulation of adenosine and tryptophan, 5) direct killing of effector T cells (8,9). Thus, Treg cells can infiltrate the tumor microenvironment andinhibit the antitumor immune response after becoming activated. Therefore, strategies that can reduce Treg cells and control their function are critical to enhancing antitumor immune responses in the field of cancer immunotherapy (9). Mesenchymal stem cells (MSCs) are derived from the mesoderm that has differentiation capacity into various tissue cells such as osteoblasts, chondrocytes, adipocytes, muscle cells, and neurocytes (10–14). Moreover, They have the ability to self-renew in vivo and in vitro under appropriate conditions (14,15). MSCs can obtain from various sources, including adipose tissue, bone marrow, skin, peripheral and umbilical cord blood, dental pulp, amniotic fluid, synovium, endometrium, dental pulp, heart, brain, umbilical cord tissue, and almost any graft tissue after delivery (16,17). They express CD90, CD73, CD105 on their surface while they not express CD14, CD45, CD11b, CD34, CD19, CD79a, and HLA-DR (18,19). In addition to modulating the immune response, MSCs also regenerate damaged tissue (14,19,20). They can migrate to the site through chemokines released from damaged tissue and eventually differentiate into mature organ cells to repair tissue (21,22). These cells are considered suitable candidates for cell therapy due to their several characteristics: a) low immunogenicity, b) easy separation from multiple tissues, and c) high reproducibility (23). Among their functional properties, MSCs can suppress adaptive immune responses either directly through inhibiting the proliferation of CD4+ helper T (Th) cells and CD8+ cytotoxic T (Tc) cells or indirectly by modulating antigen presentation via DCs (24). Recent studies showed MSCs suppress the immune system by activating Treg cells. They showed that MCSs could activate Treg cells from CD4+ T cells through four mechanisms: a) cell-to-cell contact-dependent mechanisms, b) soluble factor-dependent mechanisms [transforming growth factor beta-1 (TGF-β1), prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO), heme oxygenase-1 (HO-1), human leukocyte antigen-G5 (HLA-G5), leukemia inhibitory factor (LIF)], c) antigen presenting cell-dependent mechanisms, d) extracellular vesicle (EV)-dependent mechanisms (23). This review aimed to identify the effect of MSCs in increasing the abundance of Treg cells and suppressing their immunity against cancer.
  • Results: Result: In many studies on various sources of MSC, MSCs have been shown to modulate the function of immune cells, especially T cells, by reducing T cell proliferation and increasing the induction of Treg of active cells (24–26). Cell contact, production of soluble factors, and conversion of antigen-presenting cells into tolerable phenotypes are among the possible mechanisms used by peripheral MSCs to regulate and activate Treg activity (27,28). Factors involved in Treg differentiation by MSC are TGF-β1, PGE2, HLA-G5, IDO, HO-1, IL-10 secreted by MSC (28–32). MSCs can induce Treg cells through an indirect pathway through dendritic cells and monocytes. Maryam Khosravi et al. (33) showed that MSCs induce tolerant dendritic cells (tDCs) from dendritic cells. MSD-induced tDCs stimulate CD4+ T cells to produce an anti-inflammatory phenotype. Tolerance factors produced by tDC include retinoic acid (RA), programmed death ligand-1 (PDL-1), immunoglobulin-like transcript 3 (ILT3), TGF-β1, and IL-10. The ILT receptor found in tDCs has been shown to stimulate Treg differentiation. Recently, it has been shown that DCs induced by MSCs express ILT3, ILT4, PDL-1, IDO molecules, which increase the differentiation of immunosuppressive Treg cells. These tDCs can convert activated T cells into Treg and enhance the suppressive function of existing Tregs (34). Sara Marie Melief et al. (35) also showed the importance of monocytes in the co-culture and the Tregs differentiation by MSCs. They stated that monocytes are essential for Treg to induce by MSC, which Treg induce disrupted by removal of monocytes of culture. In addition to increasing the survival of monocytes, MSCs differentiate them into type 2 macrophages. M2 macrophages secrete high levels of CCL18 and IL-10 express CD103 and CD206. Several studies have shown that CCL18 may be responsible for inducing Treg. Several studies have shown that CCL18 can be responsible for inducing Treg (36,37). In another study, Ghada Beldi et al. (38) showed that TNF-α increases the ability of MSCs to differentiate monocytes into M2 macrophages. MSCs express TNFR2 on their surface (39). They showed that MSCs, through TNFR2, increased monocyte differentiation into M2 macrophages, increased production of IL-10, nitric oxide (NO), TGF-β1, and induced Treg cells. NO secreted by MSC is one of the major mediators of immune suppression. In the absence of TNFR2 expression in MSCs, the production of IL-10, NO, TGF-β1 occurs less by MSCs, so the resulting Tregs have a less immunosuppressive effect.
  • Conclusion: Conclusion MSCs are shown to modulate the function of immune cells, especially T cells, by reducing T cell proliferation and induction of Treg. MSCs can regulate and activate Treg activity by establishing cell to cell contact, producing soluble factors, and converting antigen-presenting cells into tolerable forms. Treg differentiation by MSC is influenced by TGF-β1, PGE2, HLA-G5, IDO, HO-1, and IL-10 secreted by MSC. MSCs can induce Treg cells indirectly via dendritic cells and monocytes. In conclusion, these findings suggest that MSCs in leukemia patients may have defects and suppress the immune system in favor of tumor cells by increasing suppressive Treg cells and increase the severity of disease by proliferation of leukemia cells in the BM and PB of leukemia patients. Further studies on the mechanism of MSCs in the treatment of leukemia patients are necessary to understand more about other function of these cells.
  • Keywords: Leukemia, Mesenchymal stem cells, Bone marrow, T cell, T regulatory cells