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Requirements of transcription factor Smad-dependent and -independent TGF-? signaling to control discrete T-cell functions.

ABSTRACT: TGF-? modulates immune response by suppressing non-regulatory T (Treg) function and promoting Treg function. The question of whether TGF-? achieves distinct effects on non-Treg and Treg cells through discrete signaling pathways remains outstanding. In this study, we investigated the requirements of Smad-dependent and -independent TGF-? signaling for T-cell function. Smad2 and Smad3 double deficiency in T cells led to lethal inflammatory disorder in mice. Non-Treg cells were spontaneously activated and produced effector cytokines in vivo on deletion of both Smad2 and Smad3. In addition, TGF-? failed to suppress T helper differentiation efficiently and to promote induced Treg generation of non-Treg cells lacking both Smad2 and Smad3, suggesting that Smad-dependent signaling is obligatory to mediate TGF-? function in non-Treg cells. Unexpectedly, however, the development, homeostasis, and function of Treg cells remained intact in the absence of Smad2 and Smad3, suggesting that the Smad-independent pathway is important for Treg function. Indeed, Treg-specific deletion of TGF-?-activated kinase 1 led to failed Treg homeostasis and lethal immune disorder in mice. Therefore, Smad-dependent and -independent TGF-? signaling discretely controls non-Treg and Treg function to modulate immune tolerance and immune homeostasis.

SUBMITTER: Gu AD

PROVIDER: S-EPMC3271895 | biostudies-other | 2012 Jan

REPOSITORIES: biostudies-other

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Requirements of transcription factor Smad-dependent and -independent TGF-β signaling to control discrete T-cell functions.

Gu Ai-Di AD Wang Yunqi Y Lin Lin L Zhang Song S SS Wan Yisong Y YY

Proceedings of the National Academy of Sciences of the United States of America 20120104 3

TGF-β modulates immune response by suppressing non-regulatory T (Treg) function and promoting Treg function. The question of whether TGF-β achieves distinct effects on non-Treg and Treg cells through discrete signaling pathways remains outstanding. In this study, we investigated the requirements of Smad-dependent and -independent TGF-β signaling for T-cell function. Smad2 and Smad3 double deficiency in T cells led to lethal inflammatory disorder in mice. Non-Treg cells were spontaneously activat ...[more]

PMID: 22219364

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Project description:Hepatocellular carcinoma (HCC) is a major public health problem due to increased incidence, late diagnosis and limited treatment options. TGF-? is known to provide cytostatic signals during early stages of liver damage and regeneration, but exerts tumor promoting effects in onset and progression of liver cancer. To understand the mechanistic background of such a switch, we systematically correlated loss of cytostatic TGF-? effects with strength and dynamics of its downstream signaling in 10 HCC cell lines. We demonstrate that TGF-? inhibits proliferation and induces apoptosis in cell lines with low endogenous levels of TGF-? and Smad7 and strong transcriptional Smad3 activity (PLC/PRF/5, HepG2, Hep3B, HuH7), previously characterized to express early TGF-? signatures correlated with better outcome in HCC patients. TGF-? dependent cytostasis is blunted in another group of cell lines (HLE, HLF, FLC-4) expressing high amounts of TGF-? and Smad7 and showing significantly reduced Smad3 signaling. Of those, HLE and HLF exhibit late TGF-? signatures, which is associated with bad prognosis in HCC patients. RNAi with Smad3 blunted cytostatic effects in PLC/PRF/5, Hep3B and HuH7. HCC-M and HCC-T represent a third group of cell lines lacking cytostatic TGF-? signaling despite strong and prolonged Smad3 phosphorylation and low Smad7 and TGF-? expression. Inhibitory linker phosphorylation, as in HCC-T, may disrupt C-terminally phosphorylated Smad3 function. In summary, we assort 10 HCC cell lines in at least two clusters with respect to TGF-? sensitivity. Cell lines responsive to the TGF-? cytostatic program, which recapitulate early stage of liver carcinogenesis exhibit transcriptional Smad3 activity. Those with disturbed TGF-?/Smad3 signaling are insensitive to TGF-? dependent cytostasis and might represent late stage of the disease. Regulation of this switch remains complex and cell line specific. These features may be relevant to discriminate stage dependent TGF-? functions for the design of efficient TGF-? directed therapy in liver cancer.

Dataset Information

Requirements of transcription factor Smad-dependent and -independent TGF-? signaling to control discrete T-cell functions.

Publications

Requirements of transcription factor Smad-dependent and -independent TGF-β signaling to control discrete T-cell functions.

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