Centre de recherche, Hôpital Maisonneuve-Rosemont, and Department of Medicine, University of Montreal, Montréal, Quebec, Canada.
Genes Immun. 2013 Mar;14(2):115-26. doi: 10.1038/gene.2012.63. Epub 2013 Jan 17.
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.
转化生长因子-β（TGF-β）通过对 T 细胞反应的组成性抑制作用来维持自身耐受。在大多数生理情况下，TGF-β的耐受作用取决于经典信号分子 Smad3。为了描述 TGF-β/Smad3 信号如何有助于维持 T 细胞耐受，我们研究了 TGF-β/Smad3 信号在静止或激活的 CD4 T 细胞下游的转录谱。我们报告说，在 TGF-β存在的情况下，Smad3 调节>400 个转录本的表达。值得注意的是，我们鉴定出 40 个转录本，其在静止和激活细胞中均表现出 Smad3 依赖性表达。该“特征”证实了 Smad3 在 TGF-β生物学中的非冗余作用，并鉴定了已知和潜在的免疫调节基因。此外，我们提供了基因组和功能证据，表明 TGF-β/Smad3 途径调节 T 细胞激活和代谢。特别是，我们表明 TGF-β/Smad3 信号会抑制 CD28 刺激对 T 细胞生长和增殖的影响。TGF-β/Smad3 信号对 T 细胞激活的影响与 mTOR 抑制剂雷帕霉素相似。考虑到共刺激对 T 细胞激活结果的重要性，我们提出 TGF-β-Smad3 信号可能通过抑制共刺激依赖性合成代谢途径的动员来维持 T 细胞耐受。
