Introduction. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease driven by aberrant responses in both innate and adaptive immunity.1 Standard treatment consists of immunosuppressive agents such as corticosteroids, azathioprine, and methotrexate.2 When these therapies fail, mesenchymal stem cells (MSCs) offer promise: by modulating the immune system, they are able to notably suppress T cell proliferation and offer therapeutic benefit in lupus and other autoimmune diseases.2,3,4 However, such therapy places MSCs in an inflammatory environment. Recent studies have drawn attention to the effect of inflammatory factors on MSC function.4,5,6 The inflammatory mediator IFN-γ has been shown to initiate the increased 2,3-indolamine dioxygenase (IDO) expression of MSCs through a pathway involving PI3Ka and STAT1.5 IDO is responsible for the MSC inhibition of T-cell proliferation.4 Understanding the mechanisms behind MSC therapy in the context of various disease states is integral in harnessing their immunomodulatory ability. Methods. UC-MSCs and PBMCs (peripheral blood mononuclear cells) isolated from patients with active SLE were co-cultured with an inhibitor of the IDO enzyme (1-methyl-dl-tryptophan) and then CD4+T cells measured. CD4/CD8 cells were then separated, IDO and IFN- γ expression were quantified by Western Blot analysis, and antibody to IFN-γ added to assess effect on IDO production.4 In a second study, researchers performed knockdown of PI3K and STAT1 by siRNA transfection and resultant mRNA expression of IDO was determined by RT-PCR. Western Blot was used to analyze IFN-γ induced phosphorylation of STAT1.5 Results. UC-MSCs significantly inhibit proliferation of CD4+25- T lymphocytes in lupus patients; furthermore; the IDO inhibitor reversed the suppression of lupus T-cell proliferation by the UC-MSCs. IFN-γ from lupus CD8+ T-cells triggered allogenic MSCs to produce IDO and inhibit T cell proliferation. The increase in IDO activity was seen post MSC transplantation in lupus patients.4 Secondly, it was determined that PI3K is required for IFN-γ induced IDO production. STAT1 requires phosphorylation to be translocated to the nucleus, and IFN-γ stimulation caused this phosphorylation to occur. Overexpression of both players, PI3K and STAT1, increased IDO production.5 Conclusions. These studies highlight IFN-γ as the inflammatory factor that primes MSCs to function in the inhibition of T-cell proliferation in lupus patients. IFN-γ works through PI3K for the ultimate phosphorylation of the transcription factor STAT1, which in turn causes increased expression of IDO from MSCs and regulation of the immune system.3,4,5. As MSCs show promise in clinical application, how they function within a SLE patient’s system should not be overlooked.7
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- Wang D, Feng X, Lu L, et. al. A CD8 T cell/indoleamine 2,3-dioxygenase axis is required for mesenchymal stem cell suppression of human systemic lupus erythematosus. Arthritis Rheumatol. 2014 Aug;66(8):2234-45.
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- Jitschin R, Bottcher M, Saul D, et al. Inflammation-induced glycolytic switch controls suppressivity of mesenchymal stem cells via STAT1 glycosylation. Leukemia. 2019. doi: 10.1038/s41375-018-0376-6.
- Yang X, Yang J, Li X, Ma W, Zou H. Bone marrow-derived mesenchymal stem cells inhibit T follicular helper cells in lupus-prone mice. Lupus. 2018 Jan;27(1):49-59.