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

Transforming growth factor-beta (TGF-beta) maintains self-tolerance through a constitutive inhibitory effect on T-cell reactivity. In most physiological situations, the tolerogenic effects of TGF-beta depend on the canonical signaling molecule Smad3. To characterize how TGF-beta/Smad3 signaling contributes to maintenance of T-cell tolerance, we characterized the transcriptional landscape downstream. of TGF-beta/Smad3 signaling in resting or activated CD4 T cells. We report that in the presence of TGF-beta, 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-beta biology and identified both known and putative immunoregulatory genes. Moreover, we provide genomic and functional evidence that the TGF-beta/Smad3 pathway regulates 1-cell activation and metabolism. In particular, we show that TGF-beta/Smad3 signaling dampens the effect of CD28 stimulation on 1-cell growth and proliferation. The impact of TGF-beta/Smad3 signals on 1-cell activation was similar to that of the mTOR inhibitor Rapamycin. Considering the importance of co-stimulation on the outcome of 1-cell activation, we propose that TGF-beta-Smad3 signaling may maintain 1-cell tolerance by suppressing co-stimulation-dependent mobilization of anabolic pathways. Genes and Immunity (2013) 14, 115-126; doi:10.1038/gene.2012.63; published online 17 January 2013