Tolerogenic dendritic cells generated with dexamethasone and vitamin D3 regulate rheumatoid arthritis CD4+ T cells partly via transforming growth factor-β1
Tolerogenic dendritic cells generated with dexamethasone and vitamin D3 regulate rheumatoid arthritis CD4+ T cells partly via transforming growth factor-β1
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DOI：
10.1111/cei.12870
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发表时间：
2017-01-01
影响因子：
4.6
通讯作者：
Hilkens, C. M. U.
中科院分区：
文献类型：
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作者：
Anderson, A. E.;Swan, D. J.;Hilkens, C. M. U.
致耐受性树突状细胞（tolDC）是治疗类风湿性关节炎（RA）和其他自身免疫性疾病的新的免疫工具。我们已经建立了通过药理学调节人单核细胞衍生的DC来产生稳定的tolDC的方法。这些tolDC对CD 4（+）T细胞发挥有效的促耐受性作用。缺乏白细胞介素（IL）-212p70产生是tolDC的关键免疫调节属性，但不能完全解释它们的作用。在这里，我们表明tolDC在mRNA和蛋白质水平上表达转化生长因子（TGF）-β 1，并且这种免疫调节细胞因子的表达在tolDC中显著高于成熟单核细胞来源的DC。通过抑制TGF-β 1信号传导，我们证明tolDC以至少部分依赖于这种细胞因子的方式调节CD 4（+）T细胞应答。重要的是，我们还表明，虽然RA患者和健康对照的CD 4（+）T细胞上TGF β R Ⅱ的表达没有显著差异，但RA患者CD 4（+）T细胞对TGF β 1的反应性明显低于健康对照CD 4（+）T细胞[TGF β诱导的母体对十肢瘫痪同源物（Smad）2/3磷酸化的反应性降低，叉头盒蛋白3（FoxP 3）表达和（IFN）-γ分泌的抑制]。然而，尽管如此，来自RA患者的CD 4（+）T细胞可以以TGF-β 1依赖性方式被tolDC有效调节。这项工作对于未来研究tolDC作为治疗RA的新型免疫疗法的潜在用途的设计和开发是重要的。
Tolerogenic dendritic cells (tolDC) are a new immunotherapeutic tool for the treatment of rheumatoid arthritis (RA) and other autoimmune disorders. We have established a method to generate stable tolDC by pharmacological modulation of human monocyte-derived DC. These tolDC exert potent pro-tolerogenic actions on CD4(+) T cells. Lack of interleukin (IL)-212p70 production is a key immunoregulatory attribute of tolDC but does not explain their action fully. Here we show that tolDC express transforming growth factor (TGF)-beta 1 at both mRNA and protein levels, and that expression of this immunoregulatory cytokine is significantly higher in tolDC than in mature monocyte-derived DC. By inhibiting TGF-beta 1 signalling we demonstrate that tolDC regulate CD4(+) T cell responses in a manner that is at least partly dependent upon this cytokine. Crucially, we also show that while there is no significant difference in expression of TGFbRII on CD4(+) T cells from RA patients and healthy controls, RA patient CD4(+) T cells are measurably less responsive to TGF-beta 1 than healthy control CD4(+) T cells [reduced TGF-beta-induced mothers against decapentaplegic homologue (Smad) 2/3 phosphorylation, forkhead box protein 3 (FoxP3) expression and suppression of (IFN)-gamma secretion]. However, CD4(+) T cells from RA patients can, nonetheless, be regulated efficiently by tolDC in a TGF-beta 1-dependent manner. This work is important for the design and development of future studies investigating the potential use of tolDC as a novel immunotherapy for the treatment of RA.