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TGF-? converts Th1 cells into Th17 cells through stimulation of Runx1 expression.

ABSTRACT: Differentiated CD4(+) T cells preserve plasticity under various conditions. However, the stability of Th1 cells is unclear, as is whether Th1 cells can convert into Th17 cells and thereby contribute to the generation of IFN-?(+) IL-17(+) CD4(+) T cells, the number of which correlates with severity of colitis. We investigated whether IFN-?(+) Th1 cells can convert into Th17 cells under intestinal inflammation and the mechanisms involved. IFN-?(Thy1.1+) Th1 cells were generated by culturing naïve CD4(+) T cells from IFN-?(Thy1.1) CBir1 TCR-Tg reporter mice, whose TCR is specific for an immunodominant microbiota antigen, CBir1 flagellin, under Th1 polarizing conditions. IFN-?(Thy1.1+) Th1 cells induced colitis in Rag(-/-) mice after adoptive transfer and converted into IL-17(+) Th17, but not Foxp3(+) Treg cells in the inflamed intestines. TGF-? and IL-6, but not IL-1? and IL-23, regulated Th1 conversion into Th17 cells. TGF-? induction of transcriptional factor Runx1 is crucial for the conversion, since silencing Runx1 by siRNA inhibited Th1 conversion into Th17 cells. Furthermore, TGF-? enhanced histone H3K9 acetylation but inhibited H3K9 trimethylation of Runx1- and ROR-?t-binding sites on il-17 or rorc gene in Th1 cells. We conclude that Th1 cells convert into Th17 cells under inflammatory conditions in intestines, which is possibly mediated by TGF-? induction of Runx1.

SUBMITTER: Liu HP

PROVIDER: S-EPMC4441226 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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TGF-β converts Th1 cells into Th17 cells through stimulation of Runx1 expression.

Liu Hou-Pu HP Cao Anthony T AT Feng Ting T Li Qingjie Q Zhang Wenbo W Yao Suxia S Dann Sara M SM Elson Charles O CO Cong Yingzi Y

European journal of immunology 20150211 4

Differentiated CD4(+) T cells preserve plasticity under various conditions. However, the stability of Th1 cells is unclear, as is whether Th1 cells can convert into Th17 cells and thereby contribute to the generation of IFN-γ(+) IL-17(+) CD4(+) T cells, the number of which correlates with severity of colitis. We investigated whether IFN-γ(+) Th1 cells can convert into Th17 cells under intestinal inflammation and the mechanisms involved. IFN-γ(Thy1.1+) Th1 cells were generated by culturing naïve ...[more]

PMID: 25605286

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Project description:: Human mesenchymal stem cells (hMSCs) are being increasingly pursued as potential therapies for immune-mediated conditions, including multiple sclerosis. Although they can suppress human Th1 responses, they reportedly can reciprocally enhance human Th17 responses. Here, we investigated the mechanisms underlying the capacity of hMSCs to modulate human Th1 and Th17 responses. Human adult bone marrow-derived MSCs were isolated, and their purity and differentiation capacity were confirmed. Human venous peripheral blood mononuclear cells (PBMC) were activated, alone, together with hMSC, or in the presence of hMSC-derived supernatants (sups). Cytokine expression by CD4+ T-cell subsets (intracellular staining by fluorescence-activated cell sorting) and secreted cytokines (enzyme-linked immunosorbent assay) were then quantified. The contribution of prostaglandin E2 (PGE2) as well as of myeloid cells to the hMSC-mediated regulation of T-cell responses was investigated by selective depletion of PGE2 from the hMSC sups (anti-PGE2 beads) and by the selective removal of CD14+ cells from the PBMC (magnetic-activated cell sorting separation). Human MSC-secreted products could reciprocally induce interleukin-17 expression while decreasing interferon-γ expression by human CD4+ T cells, both in coculture and through soluble products. Pre-exposure of hMSCs to IL-1β accentuated their capacity to reciprocally regulate Th1 and Th17 responses. Human MSCs secreted high levels of PGE2, which correlated with their capacity to regulate the T-cell responses. Selective removal of PGE2 from the hMSC supernatants abrogated the impact of hMSC on the T cells. Selective removal of CD14+ cells from the PBMCs also limited the capacity of hMSC-secreted PGE2 to affect T-cell responses. Our discovery of a novel PGE2-dependent and myeloid cell-mediated mechanism by which human MSCs can reciprocally induce human Th17 while suppressing Th1 responses has implications for the use of, as well as monitoring of, MSCs as a potential therapeutic for patients with multiple sclerosis and other immune-mediated diseases.SignificanceAlthough animal studies have generated a growing interest in the anti-inflammatory potential of mesenchymal stem cells (MSCs) for the treatment of autoimmune diseases, MSCs possess the capacity to both limit and promote immune responses. Yet relatively little is known about human-MSC modulation of human disease-implicated T-cell responses, or the mechanisms underlying such modulation. The current study reveals a novel prostaglandin E2-dependent and myeloid cell-mediated mechanism by which human MSCs can reciprocally regulate human Th17 and Th1 responses, with implications for the use of MSCs as a potential therapeutic for patients with multiple sclerosis and other immune-mediated diseases.

Dataset Information

TGF-? converts Th1 cells into Th17 cells through stimulation of Runx1 expression.

Publications

TGF-β converts Th1 cells into Th17 cells through stimulation of Runx1 expression.

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