Mesenchymal stem cells promote neutrophil activation by inducing IL-17 production in CD4+ CD45RO+ T cells
Introduction
Mesenchymal stem cells (MSCs) are multi-potent cells that can differentiate into the osteogenic, chrondrogenic and adipogenic lineages. They are non-hematopoietic stem cells that represent 0.01–0.001% of bone marrow cells (Chamberlain et al. 2007). The interaction of MSCs with cells of both the innate and adaptive immune systems can modulate several effector functions (Uccelli et al., 2006, Uccelli et al., 2008). Compelling evidence has shown that MSCs exert immunosuppressive effects on T (Aggarwal and Pittenger, 2005, Glennie et al., 2005, Sato et al., 2007, Zappia et al., 2005), B (Corcione et al. 2006), NK (Sotiropoulou et al., 2006, Spaggiari et al., 2008), and dendritic cells (Aggarwal and Pittenger, 2005, Chen et al., 2007, Ramasamy et al., 2007). Several studies have shown that the immunosuppressive properties of MSCs have therapeutic benefits in autoimmune (Rafei et al., 2009, Zappia et al., 2005, Zhang et al., 2011) and graft-versus-host diseases (Le Blanc et al. 2004) in clinical settings. However, conflicting results have also been reported by independent research groups regarding the effect of MSCs on collagen-induced arthritis (Chen et al., 2010, Djouad et al., 2005) and graft-versus-host diseases (Sudres et al. 2006). These studies do not support the notion that MSCs have sufficient immunosuppressive potential in vivo for clinical applications. Although the underlying reasons for these contradictory results are at present unexplained, they may be due to the heterogeneous nature of the MSC populations that have been studied.
IL-17 is recognized as an inflammatory cytokine. It is believed that IL-17 is mainly secreted by Th17 cells. The biological functions of IL-17 have been widely studied since its identification. Accumulating evidence has shown that IL-17 plays a central role in the cytokine networks that coordinate innate and adaptive immunity (Weaver et al., 2007, Xu and Cao, 2010). It has been clearly shown that the combination of TGF-β and IL-6 is critical for the differentiation of activated T lymphocytes into Th17 cell lineage in mice, whereby the regulation of IL-17 production from cellular interactions between T and non-T cells remains unclear. A better understanding of how IL-17 production is regulated by Th17 cellular interactions may significantly impact our ability to clinically modulate immunity.
As part of the bone marrow stromal microenvironment, MSCs closely interact with hematopoietic stem cells (HSCs) and support their growth and differentiation. There is a general consensus that MSCs are one of the main cell types that contribute to the bone marrow HSC niche (Ehninger and Trumpp 2011). MSCs can facilitate the expansion of Th17 cells and up-regulate IL-17 production (Guo et al. 2009). In addition, IL-17 has been shown to increase neutrophil counts via the induction of granulocyte colony-stimulating factor (Forlow et al., 2001, Schwarzenberger et al., 1998). Thus, we hypothesized that the modulation of IL-17 production by MSCs could have a marked impact on neutrophil maturation and activation.
The objective of this study was to elucidate the role(s) and effect(s) of human bone marrow-derived MSCs (BM-MSCs) on IL-17 production. Our results demonstrate that direct cell contact of BM-MSCs with activated CD4+ CD45RO+ memory T cells, but not with other CD4+ or CD8+ T-cell subsets, induces the production of IL-17. Induction of IL-17 can further activate neutrophils to enhance their phagocytic ability. These findings suggest that MSCs play an important role in bridging adaptive and innate immune responses.
Section snippets
Culture of human BM-MSCs
Isolation of human MSCs from bone marrow was performed using a previously reported protocol (Lee et al. 2004). Human MSCs were cultured in an expansion medium consisting of Iscove's modified Dulbecco's medium (IMDM, Sigma–Aldrich, St. Louis, MO, USA) and 10% fetal bovine serum (FBS, Hyclone, Logan, UT, USA), supplemented with 10 ng/mL bFGF (R&D Systems, Minneapolis, MN, USA), 100 U/mL penicillin, 100 μg/mL streptomycin, and 2 mM l-glutamine (Sigma–Aldrich). Human BM-MSCs at passages 7–10 were used
Production of IL-17 is markedly increased in the co-cultured supernatants of mesenchymal stem cells and activated T cells
Levels of IL-17 mRNA were determined by real-time PCR from co-cultures of human BM-MSCs and human peripheral blood purified CD3+ T cells stimulated with or without anti-CD3/anti-CD28 antibodies. The presence of anti-CD3/anti-CD28 antibodies increased the level of IL-17 mRNA produced from mixed MSCs/T cell co-cultures by more than 10-fold (Fig. 1A). To investigate the effect of T-cell receptor signaling on IL-17 production, we analyzed the secretion profile of IL-17 in the supernatants of
Discussion
Following T-cell receptor engagement with peptide-MHC complexes, T cells proliferate and perform effector functions, such as cytokine secretion. The interaction of MSCs with T cells can modulate their effector functions. For the first time, we have unambiguously demonstrated that human BM-MSCs stimulated IL-17 production in activated CD4+CD45RO+ memory T cells but not in other CD4+ subsets or CD8+ T cells (Fig. 3B and C). This observation is in agreement with the finding that IL-17 is secreted
Acknowledgments
This study was supported by the following grants: VC-099-PP-01 and VC-100-PP-01 to HWC and VC-099-PP-03 and VC-100-PP-03 to SCH from the National Health Research Institutes. The authors thank the Core Facility of the Flow Activation Cell Sorter at the National Health Research Institutes and Miss Ya-Min Lin from the Institute of Molecular Biology of Academia Sinica for performing the sterile cell sorting. We are also grateful to Dr. John Kung and Dr. Michel Klein for critically reviewing the
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These authors equally contributed to this work.