Impact and Possible Mechanism(s) of Adipose Tissue-Derived Mesenchymal Stem Cells on T-Cell Proliferation in Patients With Rheumatic Disease

Abstract

Objectives: Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are chronic wasting, incurable rheumatic diseases of autoimmune background, in which T cells play a critical pathogenic role. Autologous adipose tissue-derived mesenchymal stem cells (ASCs) may represent an alternative therapeutic option for SLE and SSc patients, but the biology of these cells is poorly understood. Methods: Herein, we evaluated the anti-proliferative impact of ASCs of healthy donors (HD/ASCs, 5 reference cell lines), SLE patients (n = 20), and SSc patients (n = 20) on T lymphocytes. To assess the direct and indirect pathway of ASCs action, peripheral blood mononuclear cells (PBMCs) and purified CD4+ T cells of HD were activated and co-cultured in cell-to-cell contact (C-C) and transwell (T-W) conditions with untreated or cytokine (TNF + IFNΥ, TI)-licensed ASCs, then analyzed by flow cytometry to rate the proliferation response of CD8⁺ and/or CD4⁺ T cells. The concentrations of kynurenines, prostaglandin E2 (PGE₂), interleukin 10 (IL-10), and transforming growth factor β (TGFβ) were measured from culture supernatants. Specific inhibitors of these factors (1-MT, indomethacin, and cytokine-neutralizing antibody) were used to assess their contribution to anti-proliferative ASCs action. Results: All tested ASCs significantly decreased the number of proliferating CD4⁺ and CD8⁺ T cells, the number of division/proliferating cell (PI), and fold expansion (RI), and similarly upregulated kynurenines and PGE₂, but not cytokine levels, in the co-cultures with both types of target cells. However, TI-treated SLE/ASCs and SSc/ASCs exerted a slightly weaker inhibitory effect on CD4⁺ T-cell replication than their respective HD/ASCs. All ASCs acted mainly via soluble factors. Their anti-proliferative effect was stronger, and kynurenine levels were higher in the T-W condition than the C-C condition. Blocking experiments indicated an involvement of kynurenine pathway in inhibiting the number of proliferating cells, PI, and RI values as well as PGE₂ role in decreasing the number of proliferating cells. TGFβ did not contribute to ASCs anti-proliferative capabilities, while IL-10 seems to be involved in such activity of only SLE/ASCs. Conclusion: The results indicate that SLE/ASCs and SSc/ASCs retain their capability to restrain the expansion of allogeneic CD4⁺ and CD8⁺ T cells and act by similar mechanisms as ASCs of healthy donors and thus may have therapeutic value.

Keywords: T-cell proliferation; adipose-derived mesenchymal stem cells; soluble mediators; systemic lupus erythematosus; systemic sclerosis.