Hepatic Stellate Cells Inhibit T Cells through Active TGF-β1 from a Cell Surface-Bound Latent TGF-β1/GARP Complex.
Hepatic Stellate Cells Inhibit T Cells through Active TGF-β1 from a Cell Surface-Bound Latent TGF-β1/GARP Complex.
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DOI：
10.4049/jimmunol.1500139
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发表时间：
2015-09-15
期刊：
影响因子：
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通讯作者：
Lin F
中科院分区：
文献类型：
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作者：
Li Y;Kim BG;Qian S;Letterio JJ;Fung JJ;Lu L;Lin F
肝星状细胞（HSC）抑制T细胞，这一过程可以帮助肝脏维持其免疫豁免状态。HSC分泌潜伏性TGFβ1，但潜伏性TGFβ1被激活的详细机制以及它是否在HSC介导的T细胞抑制中起任何作用仍不清楚。糖蛋白A重复占优势（GARP）是活化的调节性T细胞（TcR）的表面标志物。GARP结合潜在的TGFβ1以激活其活性，这对于TGFAP抑制效应T细胞至关重要;然而，目前仍不清楚GARP是否存在于HSC上以及它是否对HSC功能有任何影响。在这项研究中，我们发现TGFβ1+/− HSC产生的TGFβ1水平降低，抑制T细胞的效力降低。我们还发现，药物或基因抑制TGFβ1信号通路降低了HSC的T细胞抑制活性。此外，使用分离的原代HSC，我们证明了GARP在HSC上组成型表达。阻断GARP功能或敲低GARP表达显著损害HSC抑制活化T细胞增殖和IFNγ产生的效力，表明GARP对于HSC抑制T细胞是重要的。这些结果证明了GARP在HSC上的意外存在及其在HSC活化潜伏TGFβ1从而抑制T细胞的能力方面的意义。我们的研究揭示了HSC介导的免疫调节的新机制，并可能用于其他疾病，如肝纤维化，涉及HSC分泌的TGFβ1。
Hepatic stellate cells (HSCs) inhibit T cells, a process that could help the liver to maintain its immunoprivileged status. HSCs secrete latent TGFβ1, but the detailed mechanisms by which latent TGFβ1 is activated and whether it plays any role in HSC-mediated T-cell suppression remain unclear. Glycoprotein A repetitions predominant (GARP) is a surface marker of activated regulatory T cells (Tregs). GARP binds latent TGFβ1 for its activation, which is critical for Tregs to suppress effector T cells; however, it is still unclear whether GARP is present on HSCs and whether it has any impact on HSC function. In this study, we found that TGFβ1+/− HSCs, which produce reduced levels of TGFβ1, showed decreased potency in inhibiting T cells. We also found that pharmaceutical or genetic inhibition of the TGFβ1 signaling pathway reduced the T-cell-inhibiting activity of HSCs. In addition, using isolated primary HSCs, we demonstrated that GARP was constitutively expressed on HSCs. Blocking GARP function or knocking down GARP expression significantly impaired the potency of HSCs to suppress the proliferation of and IFNγ production from activated T cells, suggesting that GARP is important for HSCs to inhibit T cells. These results demonstrate the unexpected presence of GARP on HSCs and its significance in regard to the ability of HSCs to activate latent TGFβ1 and thereby inhibit T cells. Our study reveals a new mechanism for HSC-mediated immune regulation and potentially for other conditions, such as liver fibrosis, that involve HSC-secreted TGFβ1.