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

Ewa Kuca-Warnawin,Ewa Kontny,Piotr Szczȩsny,Marzena Olesińska

doi:10.3389/fphys.2021.749481

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.

Highlights

Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are devastating and potentially fatal rheumatic diseases of an autoimmune background
Because mesenchymal stem/stromal cells (MSCs) are known to perform their immunosuppressive function through the release of numerous mediators (Fan et al, 2020), we focused on the role of kynurenines and prostaglandin E2 (PGE2) and SLE- and SSc-related cytokines, IL-10 and transforming growth factor β (TGFβ), respectively
We report that adipose tissue-derived MSCs (ASCs) obtained from SLE or SSc patients have preserved the capability to sufficiently inhibit the proliferation of two main T-cell subsets (CD4+ and CD8+) through direct and indirect ways

Summary

Introduction

Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are devastating and potentially fatal rheumatic diseases of an autoimmune background. In SLE and SSc, various T-cell subsets play a critical pathogenic role by generating and maintaining the autoimmune response, providing help to B-cells, amplifying systemic inflammation, and contributing to tissue and organ damage (Moulton et al, 2017; Varga et al, 2017; Asano and Varga, 2020; Tsai et al, 2020; Tsokos, 2020; Chen and Tsokos, 2021). The presence of both CD4+ and CD8+ T cells in the affected tissues was confirmed in SLE patients (Li et al, 2007; Cohen et al, 2008; Crispin et al, 2008) and SSc patients (Almeida et al, 2015; Liu et al, 2016; Fuschiotti, 2018a,b). The excessive proliferation of CD4+, CD8+, and double-negative (CD4−CD8−) T lymphocytes was observed in murine models of lupus and SLE patients (Tang et al, 2009; Balomenos et al, 2017; Du et al, 2019), while increased proliferation rate of naive and functionally differentiated CD4+ T cells was detected in SSc patients (Giovanetti et al, 2010)

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