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The TGF-β-Smad3 pathway inhibits CD28-dependent cell growth and proliferation of CD4 T cells

Genes & Immunity volume 14, pages 115–126 (2013)Cite this article

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An Erratum to this article was published on 07 March 2013

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Abstract

Transforming growth factor-β (TGF-β) maintains self-tolerance through a constitutive inhibitory effect on T-cell reactivity. In most physiological situations, the tolerogenic effects of TGF-β depend on the canonical signaling molecule Smad3. To characterize how TGF-β/Smad3 signaling contributes to maintenance of T-cell tolerance, we characterized the transcriptional landscape downstream of TGF-β/Smad3 signaling in resting or activated CD4 T cells. We report that in the presence of TGF-β, Smad3 modulates the expression of >400 transcripts. Notably, we identified 40 transcripts whose expression showed Smad3 dependence in both resting and activated cells. This ‘signature’ confirmed the non-redundant role of Smad3 in TGF-β biology and identified both known and putative immunoregulatory genes. Moreover, we provide genomic and functional evidence that the TGF-β/Smad3 pathway regulates T-cell activation and metabolism. In particular, we show that TGF-β/Smad3 signaling dampens the effect of CD28 stimulation on T-cell growth and proliferation. The impact of TGF-β/Smad3 signals on T-cell activation was similar to that of the mTOR inhibitor Rapamycin. Considering the importance of co-stimulation on the outcome of T-cell activation, we propose that TGF-β-Smad3 signaling may maintain T-cell tolerance by suppressing co-stimulation-dependent mobilization of anabolic pathways.

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Gene Expression Omnibus

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  • 07 March 2013

    This article has been corrected since Advance Online Publication and an erratum is also printed in this issue.

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Acknowledgements

This work was supported through grants held by JSD (Leukemia/lymphoma society of Canada (LLSC) and the Maisonneuve-Rosemont hospital foundation) as well as by an LLSC grant to CP. JSD holds a career award from the Fonds de recherche du Québec-Santé (FRQS) and Claude Perreault holds a Canada research chair in immunobiology. We would like to thank the animal care facility personnel both at the IRIC and CR-HMR as well as Danièle Gagné, Gaël Dulude and Martine Dupuis for cell sorting.

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  1. J-S Delisle and M Giroux: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre de recherche, Hôpital Maisonneuve-Rosemont (CR-HMR), Montréal, Quebec, Canada

    J-S Delisle & M Giroux

  2. Division of Hematology, Hôpital Maisonneuve-Rosemont, Montréal, Quebec, Canada

    J-S Delisle & C Perreault

  3. Department of Medicine, University of Montreal, Montréal, Quebec, Canada

    J-S Delisle & C Perreault

  4. Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montréal, Quebec, Canada

    G Boucher, J-R Landry, M-P Hardy, S Lemieux, B T Wilhelm & C Perreault

  5. Department of Physiology, Goodman Cancer Research Center, McGill University, Montréal, Quebec, Canada

    R G Jones

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  1. J-S Delisle
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Correspondence to J-S Delisle.

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Delisle, JS., Giroux, M., Boucher, G. et al. The TGF-β-Smad3 pathway inhibits CD28-dependent cell growth and proliferation of CD4 T cells. Genes Immun 14, 115–126 (2013). https://doi.org/10.1038/gene.2012.63

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