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

被引：71

作者：

Delisle, J-S ^{[1
,2
,3
]}

Giroux, M. ^{[1
]}

Boucher, G. ^{[4
]}

Landry, J-R ^{[4
]}

Hardy, M-P ^{[4
]}

Lemieux, S. ^{[4
]}

Jones, R. G. ^{[5
]}

Wilhelm, B. T. ^{[4
]}

Perreault, C. ^{[2
,3
,4
]}

机构：

[1] Hop Maisonneuve Rosemont CR HMR, Ctr Rech, Montreal, PQ, Canada

[2] Hop Maison Neuve Rosemont, Div Hematol, Montreal, PQ, Canada

[3] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada

[4] Univ Montreal, Inst Res Immunol & Canc IRIC, Montreal, PQ, Canada

[5] McGill Univ, Dept Physiol, Goodman Canc Res Ctr, Montreal, PQ, Canada

来源：

GENES AND IMMUNITY | 2013年 / 14卷 / 02期

关键词：

CD4 T cell; mTOR; T-cell metabolism; T-cell tolerance; TGF-beta; TRANSCRIPTION FACTORS CONTROL; VERSUS-HOST-DISEASE; TGF-BETA; SIGNAL-TRANSDUCTION; CYCLE PROGRESSION; MAMMALIAN TARGET; IMMUNE-RESPONSES; FOXP3; EXPRESSION; GENE-EXPRESSION; FACTOR-I;

D O I：

10.1038/gene.2012.63

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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

引用

页码：115 / 126

页数：12

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