Interaction of Human Mesenchymal Stem Cells with Alloantigen-Induced T Lymphocyte Activation Favors the Differentiation of CD4+ T Cell Subsets Expressing CD25 and/or CTLA4 Molecules.

Abstract

Experimental evidence and preliminary clinical studies have demonstrated that human mesenchymal stem cells (MSCs) display important immune modulatory function of potential relevant interest in the setting of allogeneic hematopoietic stem cell (HSC) transplantation. Effectiveness of MSCs in controlling severe GVHD seems to be related to the immune-regulatory role they play in suppressing alloantigen-specific T-cell activation. Aim of the present study was to extend the analysis of the mechanisms responsible for the immune regulatory effect of interaction between MSCs and alloantigen-specific immune response elicited in vitro in primary and in secondary mixed lymphocyte culture (MLC). At difference with most previously reported studies, we decided to employ non-irradiated MSCs, reasoning that irradiation might impair, beside the proliferative capacity, also the differentiation capability of MSCs and, consequently, alter their interaction pattern with lymphocyte subsets. MSC were added to primary MLC at different doses (MLC-responder-PBMC:MSC ratios = 1:1 and 10:1). Dendritic cell (DC) differentiation, lymphocyte proliferation, alloantigen-specific cytotoxic activity and differentiation of CD4+ T-cell subsets expressing CD25 and/or CTLA4 antigens were assessed in primary and secondary MLC, comparing the effect observed using third-party MSCs with that obtained employing autologous to the MLC-responder (autologous) MSCs. Results demonstrated that human MSCs: (1) strongly inhibit alloantigen-induced DC1 differentiation; (2) down-regulate, in a dose-dependent manner, alloantigen-induced lymphocyte expansion, especially that of CD8+ T cells and of NK lymphocytes; (3) favor the differentiation of CD4+ T cells co-expressing CD25 and/or CTLA4, a phenotype associated with regulatory/suppressive function of immune response; (4) cause a dose-dependent reduction of alloantigen-specific cytotoxic capacity mediated by either cytotoxic T lymphocytes or NK cells; (5) exert more effective suppressive activity on MLC-induced T-cell activation when they are allogeneic rather than autologous with respect to responder cells. In particular, higher percentages of CD4+ and of CD4+CD25+ T cells co-expressing CTLA4+ were detected when third-party, rather than autologous, MSCs were added to MLC. These data suggest that T-cell recognition of alloantigens expressed by MSCs may further facilitate the preferential differentiation of activated CD4+ T cells expressing CTLA4, a glycoprotein, known to deliver an inhibitory signal to T cells and to mediate apoptosis of previously activated T lymphocytes. Several studies previously demonstrated that MSCs exert inhibitory effect on lymphocyte activation through the release of soluble factors. Our data suggest that the preferential differentiation of CD4+CD25+ regulatory T-cell subsets may be favored by other mechanisms of MSC-mediated inhibition of alloantigen-induced effector cell activation and expansion, and, in turn, these CD4+CD25+ cells contribute to propagate and extend suppressor activity. Altogether, our results provide immunological support to the use of MSCs for prevention of immune complications related to both HSC and solid organ transplantation and to the theory that MSCs are “universal” suppressors of immune reactivity.

The immunomodulatory effects of adipose‐derived mesenchymal stem cells and mesenchymal stem cells‐conditioned medium in chronic colitis

“…A significant increase in Treg cell percentage was also observed in spleen in the ADMSCs group as compared with the controls (P < 0.05). This finding confirmed the induction of Treg cells by ADMSCs, which wasreported in other studies as well(Maccario et al, 2005;Prevosto, Zancolli, Canevali, Zocchi, & Poggi, 2007;Selmani et al, 2008) González et al (2009). observed the stimulatory effect of human ADMSCs and mouse ADMSC injections on Treg cell differentiation in the TNBS-induced IBD model.…”

Mesenchymal stromal cells: a key player in ‘innate tolerance’?

“…Further evidence of Treg-cell activation has been achieved in solid organ transplantation whereby the administration of MSC was observed to favour the differentiation of donor-specific Treg cells. [36][37][38][39][40] In models of autoimmune diseases, MSC effectively prevent the bone and cartilage damage produced by collagen-induced arthritis and such an effect is associated with the in vivo induction of antigen-specific Treg cells. 41 Similarly, human MSC stimulate IL-10producing T cells and FoxP3 + CD4 + CD25 + T cells, with the capacity to suppress collagen-specific T-cell responses.…”

Selected Stro‐1‐enriched bone marrow stromal cells display a major suppressive effect on lymphocyte proliferation

“…Bone marrow (BM) stromal cells; referred as mesenchymal stem cells (MSCs) have been shown to possess immunomodulatory properties. They are able to suppress allogeneic responses in a mixed lymphocyte reaction (MLR; Di Nicola et al, 2002;Bartholomew et al, 2002;Potian et al, 2003;Tse et al, 2003;Le Blanc et al, 2003, 2004aDjouad et al, 2003;Maitra et al, 2004;Aggarwal & Pittenger, 2005) and modify antigen-presenting cell (APC) maturation in vitro (Zhang et al, 2004;Beyth et al, 2005;Jiang et al, 2005;Maccario et al, 2005). Their immune-inhibitory effects have been demonstrated in vitro and in vivo in primate (Bartholomew et al, 2002), murine (Djouad et al, 2003), and in human, where MSCs has been used to treat severe graft-vs.-host disease (GVHD; Le Blanc et al, 2004b).…”