Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli

Abstract

CD2 ؉ T lymphocytes obtained from either the donor of bone marrow stromal cells (BMSCs) or a third party were cultured in mixed lymphocyte reactions (MLRs) with either allogeneic dendritic cells (DCs) or peripheral blood lymphocytes (PBLs). When autologous or allogeneic BMSCs were added back to T cells stimulated by DCs or PBLs, a significant and dosedependent reduction of T-cell proliferation, ranging from 60% ؎ 5% to 98% ؎ 1%, was evident. Similarly, addition of BMSCs to T cells stimulated by polyclonal activators resulted in a 65% ؎ 5% (P ‫؍‬ .0001) suppression of proliferation. BMSCinduced T-cell suppression was still evident when BMSCs were added in culture as late as 5 days after starting of MLRs. BMSC-inhibited T lymphocytes were not apoptotic and efficiently proliferated on restimulation. BMSCs significantly suppressed both CD4 ؉ and CD8 ؉ T cells (65% ؎ 5%, [P ‫؍‬ .0005] and 75% ؎ 15% [P ‫؍‬ .0005], respectively). Transwell experiments, in which cell-cell contact between BMSCs and effector cells was prevented, resulted in a significant inhibition of T-lymphocyte proliferation, suggesting that soluble factors were involved in this phenomenon. By using neutralizing monoclonal antibodies, transforming growth factor ␤1 and hepatocyte growth factor were identified as the mediators of BMSC effects. In conclusion, our data demonstrate that (1) autologous or allogeneic BMSCs strongly suppress T-lymphocyte proliferation, (2) this phenomenon that is triggered by both cellular as well as nonspecific mitogenic stimuli has no immunologic restriction, and (3) T-cell inhibition is not due to induction of apoptosis and is likely due to the production of soluble factors. (Blood. 2002;99:3838-3843)

Immunoregulatory function of mesenchymal stem cells

“…Despite the general consensus concerning the capacity of MSC to inhibit proliferation of T lymphocytes, little is known on the molecular mechanism(s) responsible for this effect. Thus, it did not appear to be dependent on the induction of apoptosis of proliferating cells [13,16,39]. Inhibition of cell division could be a possible explanation since accumulation of cells in the G 0 phase of the cell cycle has been detected [45].…”

“…Inhibition of T cell proliferation by MSC appears to be subsequent both to cell-to-cell interaction and to the release of soluble factors, and it is conceivable that discrepant findings reported in the literature reflect differences in the experimental conditions used [13,14,16,48,49]. TGF-b1 and HGF [13], indoleamine 2,3-dioxygenase (IDO) [50] and prostaglandin E2 (PGE-2) [46] represent MSC-derived molecules that have been proposed to exert immunomodulatory activity on T cell responses. However, most of these results need to be confirmed, and it is likely that key molecules will be identified through functional molecular profiling of the MSC transcriptome.…”

“…However, only in 2002 has it been clearly demonstrated that human MSC (i) could inhibit proliferation of T cells that had either been cultured in mixed lymphocyte reactions (MLR) or stimulated by polyclonal activators [13], and (ii) upon in vivo infusion, could prolong skin engraftment in nonhuman primates [12]. Krampera et al further demonstrated that the anti-proliferative activity of murine MSC was also exerted on antigen-specific responses [42].…”

“…Inhibition of T cell proliferation resulted in the decreased production of effector Th1 cytokines [16,42,46]; however, the expression of activation markers in T cells that have been cultured with MSC remains a controversial issue [39,43,45,47]. Inhibition of T cell proliferation by MSC appears to be subsequent both to cell-to-cell interaction and to the release of soluble factors, and it is conceivable that discrepant findings reported in the literature reflect differences in the experimental conditions used [13,14,16,48,49]. TGF-b1 and HGF [13], indoleamine 2,3-dioxygenase (IDO) [50] and prostaglandin E2 (PGE-2) [46] represent MSC-derived molecules that have been proposed to exert immunomodulatory activity on T cell responses.…”

“…More recently, MSC have been shown to inhibit T cell proliferation upon antigen stimulation [12][13][14]. Since these early reports, many studies have demonstrated that MSC affect the function of different immunocompetent cell types, lending support to their pioneering utilization in acute graft-versus-host disease (GVHD) [15] and providing the rationale for their possible use in the treatment of autoimmune disorders [16].…”