title: The TGF-β-Smad3 pathway inhibits CD28-dependent cell growth and proliferation of CD4 T cells.
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.
authors: Centre de recherche, Hôpital Maisonneuve-Rosemont, and Department of Medicine, University of Montreal, Montréal, Quebec, Canada. js.delisle@umontreal.ca
authors: J-S
authors: JS
authors: Delisle
authors: M
authors: M
authors: Giroux
authors: G
authors: G
authors: Boucher
authors: J-R
authors: JR
authors: Landry
authors: M-P
authors: MP
authors: Hardy
authors: S
authors: S
authors: Lemieux
authors: R G
authors: RG
authors: Jones
authors: B T
authors: BT
authors: Wilhelm
authors: C
authors: C
authors: Perreault
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D049109:Cell Proliferation; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D018106:CD28 Antigens; D007166:Immunosuppressive Agents; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus