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

Genes Immun. 2013 Mar;14(2):115-26. doi: 10.1038/gene.2012.63. Epub 2013 Jan 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD28 Antigens / metabolism*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / physiology*
  • Cell Proliferation
  • Immunosuppressive Agents / pharmacology
  • Lymphocyte Activation
  • Mice
  • Mice, Knockout
  • Signal Transduction*
  • Sirolimus / pharmacology
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • Transforming Growth Factor beta / metabolism*

Substances

  • CD28 Antigens
  • Immunosuppressive Agents
  • Smad3 Protein
  • Smad3 protein, mouse
  • Transforming Growth Factor beta
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Sirolimus

Associated data

  • GEO/GSE40494