Interferon-γ mediates the immunosuppression of bone marrow mesenchymal stem cells on T-lymphocytes in vitro

ABSTRACT

Objectives: In the present study, we first confirmed the suppressive function of MSCs in allogeneic T cell proliferation and then examined the underlying mechanisms for MSCs’ immunomodulation and the role of the pro-inflammatory cytokine interferon (IFN)-γ.

Methods: Human MSCs were cultured in the presence or absence of IFN-γ. The expression level of prostaglandin E₂ (PGE₂), hepatocyte growth factor (HGF), transforming growth factor (TGF)-β₁ and indoleamine 2,3-dioxygenase (IDO) by MSCs were measured. T lymphocytes were isolated from peripheral blood of healthy donors and then induced to proliferate under the stimulation of anti-human CD3 mAb and anti-human CD28 mAb. In the presence of MSCs, T cell proliferation was examined by BrdU incorporation. In addition, PGE₂, HGF, TGF-β₁, Kynurenine, recombinant human IFN-γ and anti-IFN-γ mAb were added and cell proliferation was examined.

Results: Compared to the controls (MSCs alone), MSCs cocultured with IFN-γ expressed significantly higher concentrations of PGE₂, HGF and TGF-β₁. The mRNA level of IDO was remarkably increased. Human bone marrow-derived MSCs alone notably suppressed T lymphocytes proliferation in vitro. Addition of exogenous IFN-γ did not ablate the immunosuppressive effects of MSCs. Addition of anti-IFN-γ mAb partially restored suppression of T cell proliferation by MSCs.

Conclusions: Human MSCs constitutively expressed immunosuppressive levels of PGE₂, HGF and TGF-β₁. The proinflammatory cytokine IFN-γ exhibited synergistic effects with MSCs on immunosuppression, possibly by up-regulating PGE₂, HGF and TGF-β₁ in MSCs and inducting MSCs expression of IDO, involved in tryptophan catabolism.

KEYWORDS:

• Interferon-γ
• mesenchymal stem cells
• immunosuppression
• indoleamine 2,3-dioxygenase

Disclosure statement

No potential conflict of interest was reported by the authors.