Multipotent stromal cells induce human regulatory T cells through a novel pathway involving skewing of monocytes toward anti-inflammatory macrophages

Abstract

Multipotent stromal cells (MSC) have been shown to possess immunomodulatory capacities and are therefore explored as a novel cellular therapy. One of the mechanisms through which MSC modulate immune responses is by the promotion of regulatory T cell (Treg) formation. In this study, we focused on the cellular interactions and secreted factors that are essential in this process. Using an in vitro culture system, we showed that culture-expanded bone marrow-derived MSC promote the generation of CD41 T cells in human PBMC populations and that these populations are functionally suppressive. Similar results were obtained with MSC-conditioned medium, indicating that this process is dependent on soluble factors secreted by the MSC. Antibody neutralization studies showed that TGF-b1 mediates induction of Tregs. TGF-b1 is constitutively secreted by MSC, suggesting that the MSC-induced generation of Tregs by TGF-b1 was independent of the interaction between MSC and PBMC. Monocyte-depletion studies showed that monocytes are indispensable for MSC-induced Treg formation. MSC promote the survival of monocytes and induce differentiation toward macrophage type 2 cells that express CD206 and CD163 and secrete high levels of IL-10 and CCL-18, which is mediated by as yet unidentified MSC-derived soluble factors. CCL18 proved to be responsible for the observed Treg induction. These data indicate that MSC promote the generation of Tregs. Both the direct pathway through the constitutive production of TGF-b1 and the indirect novel pathway involving the differentiation of monocytes toward CCL18 producing type 2 macrophages are essential for the generation of Tregs induced by MSC.

Mesenchymal stem cells promote macrophage polarization toward M2b-like cells

“…In agreement with several earlier results [21,49,50], the crosstalk between Ms and MSCs occur primarily by soluble factors, since cytokine production during physical separation of the two cell types was similar to those measured in direct co-cultures. One of the soluble factors produced by both Ms and MSCs is PGE-2.…”

Mesenchymal stem/stromal cells precondition lung monocytes/macrophages to produce tolerance against allo- and autoimmunity in the eye

“…Of interest were the gene(s) that encode secreted proteins and were up-regulated by more than twofold in hMSCs upon coculture with lung cells (Table S1). Of the 11 up-regulated genes for secreted proteins, the following four genes have been previously shown to be associated with immunomodulatory and antiinflammatory effects of MSCs: stanniocalcin-1 (STC-1) (18), TSG-6 (4, 5, 11, 19), TGF-β (7,20,21), and prostaglandin endoperoxidase synthase 2 (PTGS-2) (10, 12, 21, 22). To examine whether any of these genes are indeed increased in the lung of mice in vivo after i.v.…”

“…Therefore, direct suppressive effects of MSCs on the immune system are short-lived, and do not explain the long-term therapeutic effects observed with MSCs in clinical and animal studies. In this context, it has been suggested that MSCs trigger a state of immune tolerance, for example, through the induction of regulatory T cells (Tregs) (6,7).…”

Adenosine production: a common path for mesenchymal stem-cell and regulatory T-cell-mediated immunosuppression

“…Indeed, MSCs are able to generate Tregs, in part, by the secretion of TGF-β and by promoting Treg expansion [61,62]. Also, it was reported that rapamycin, an inhibitor of mTOR signaling, promotes the expansion of Tregs obtained from peripheral blood, regardless if used solely or in combination with ATRA [63,64].…”