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Autocrine transforming growth factor-?1 promotes in vivo Th17 cell differentiation.

ABSTRACT: TGF-?1 is a regulatory cytokine that has an important role in controlling T cell differentiation. T cell-produced TGF-?1 acts on T cells to promote Th17 cell differentiation and the development of experimental autoimmune encephalomyelitis (EAE). However, the exact TGF-?1-producing T cell subset required for Th17 cell generation and its cellular mechanism of action remain unknown. Here we showed that deletion of the Tgfb1 gene from activated T cells and Treg cells, but not Treg cells alone, abrogated Th17 cell differentiation, resulting in almost complete protection from EAE. Furthermore, differentiation of T cells both in vitro and in vivo demonstrated that TGF-?1 was highly expressed by Th17 cells and acted in a predominantly autocrine manner to maintain Th17 cells in vivo. These findings reveal an essential role for activated T cell-produced TGF-?1 in promoting the differentiation of Th17 cells and controlling inflammatory diseases.

SUBMITTER: Gutcher I

PROVIDER: S-EPMC3690311 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Autocrine transforming growth factor-β1 promotes in vivo Th17 cell differentiation.

Gutcher Ilona I Donkor Moses K MK Ma Qian Q Rudensky Alexander Y AY Flavell Richard A RA Li Ming O MO

Immunity 20110301 3

TGF-β1 is a regulatory cytokine that has an important role in controlling T cell differentiation. T cell-produced TGF-β1 acts on T cells to promote Th17 cell differentiation and the development of experimental autoimmune encephalomyelitis (EAE). However, the exact TGF-β1-producing T cell subset required for Th17 cell generation and its cellular mechanism of action remain unknown. Here we showed that deletion of the Tgfb1 gene from activated T cells and Treg cells, but not Treg cells alone, abrog ...[more]

PMID: 21435587

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Project description:Background and aimLiver fibrosis is prevalent among chronic diseases of the liver and represents a major health burden worldwide. Growth differentiation factor 7 (GDF7), a member of the TGFβ protein superfamily, has been recently investigated for its role in repair of injured organs, but its role in chronic liver diseases remains unclear. Here, we examined hepatic GDF7 expression and its association with development and progression of human liver fibrosis. Moreover, we determined the source and target cells of GDF7 in the human liver.MethodsGDF7 expression was analyzed in fibrotic and healthy human liver tissues by immunohistochemistry and qPCR. Cell-specific accumulation of GDF7 was examined by immunofluorescence through co-staining of cell type-specific markers on formalin-fixed paraffin-embedded human liver tissues. Public single cell RNA sequence databases were analyzed for cell type-specific expression of GDF7. In vitro, human liver organoids and LX-2 hepatic stellate cells (LX-2) were treated with recombinant human GDF7. Human liver organoids were co-cultured with activated LX-2 cells to induce an autocrine signaling circuit of GDF7 in liver organoids.ResultsGDF7 protein levels were elevated in fibrotic liver tissue, mainly detected in hepatocytes and cholangiocytes. In line, GDF7 mRNA was mainly detected in liver parenchymal cells. Expressions of BMPR1A and BMPR2, encoding GDF7 receptors, were readily detected in hepatocytes, cholangiocytes and stellate cells in vivo and in vitro. In vitro, recombinant GDF7 promoted liver organoid growth and enhanced expression of the progenitor cell markers (LGR5, AXIN2), but failed to activate LX-2 cells. Still, activated LX-2 cells induced GDF7 and LGR5 expression in co-cultured human liver organoids.ConclusionsCollectively, this study reveals a role of GDF7 in liver fibrosis and suggests a potential pro-regenerative function that can be utilized for amelioration of hepatic fibrosis caused by chronic liver disease.

Project description:BackgroundThe blood-brain barrier (BBB) plays an important role as a biological barrier by regulating molecular transport between circulating blood and the brain parenchyma. In drug development, the accurate evaluation of BBB permeability is essential to predict not only the efficacy but also the safety of drugs. Recently, brain microvascular endothelial-like cells derived from human induced pluripotent stem cells (iPSCs) have attracted much attention. However, the differentiation protocol has not been optimized, and the enhancement of iPSC-derived brain microvascular endothelial-like cells (iBMELCs) function is required to develop highly functional BBB models for pharmaceutical research. Thus, we attempted to improve the functions of differentiated iBMELCs and develop a versatile BBB model by modulating TGF-β signaling pathway without implementing complex techniques such as co-culture systems.MethodsiPSCs were differentiated into iBMELCs, and TGF-β inhibitor was used in the late stage of differentiation. To investigate the effect of TGF-β on freezing-thawing, iBMELCs were frozen for 60-90 min or 1 month. The barrier integrity of iBMELCs was evaluated by transendothelial electrical resistance (TEER) values and permeability of Lucifer yellow. Characterization of iBMELCs was conducted by RT-qPCR, immunofluorescence analysis, vascular tube formation assay, and acetylated LDL uptake assay. Functions of efflux transporters were defined by intracellular accumulation of the substrates.ResultsWhen we added a TGF-β inhibitor during iBMELCs differentiation, expression of the vascular endothelial cell marker was increased and blood vessel-like structure formation was enhanced. Furthermore, TEER values were remarkably increased in three iPSC lines. Additionally, it was revealed that TGF-β pathway inhibition suppressed the damage caused by the freezing-thawing of iBMELCs.ConclusionWe succeeded in significantly enhancing the function and endothelial characteristics of iBMELCs by adding a small molecular compound, a TGF-β inhibitor. Moreover, the iBMELCs could maintain high barrier function even after freezing-thawing. Taken together, these results suggest that TGF-β pathway inhibition may be useful for developing iPSC-derived in vitro BBB models for further pharmaceutical research.

Dataset Information

Autocrine transforming growth factor-?1 promotes in vivo Th17 cell differentiation.

Publications

Autocrine transforming growth factor-β1 promotes in vivo Th17 cell differentiation.

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