Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Eur J Immunol. 2009 Nov;39(11):3147-59. doi: 10.1002/eji.200839103.
Specific therapy with modulated DC may restore immunological tolerance, thereby obviating the need for chronic immunosuppression in transplantation or autoimmunity. In this study we compared the tolerizing capacity of dexamethasone (Dex)- and 1 alpha,25-dihydroxyvitamin D3 (VD3)-modulated DC. Treatment of monocytes with either VD3 or Dex resulted in DC with stable, semi-mature phenotypes compared with standard DC, with intermediate levels of co-stimulatory and MHC class II molecules, which remained unaltered after subsequent pro-inflammatory stimulation. IL-12p70 secretion was lost by VD3- and Dex-DC, whereas IL-10 secretion was unaffected. VD3-DC distinctly produced large amounts of TNF-alpha. Both VD3- and Dex-DC possessed the capacity to convert CD4 T cells into IL-10-secreting Treg potently suppressing the proliferation of responder T cells. However, only Treg induced by VD3-DC exhibited antigen specificity. VD3-, but not Dex-, DC expressed significant high levels of PD-L1 (programmed death-1 ligand), upon activation. Blockade of PD-L1 during priming redirected T cells to produce IFN-gamma instead of IL-10 and abolished acquisition of regulatory capacity. Our findings demonstrate that both VD3- and Dex-DC possess durable but differential tolerogenic features, acting via different mechanisms. Both are potentially useful to specifically down-regulate unwanted immune responses and induce immune tolerance. These modulated DC appear suitable as adjuvant in antigen-specific clinical vaccination intervention strategies.
用调节性树突细胞（DC）进行特异性治疗可能会恢复免疫耐受，从而避免移植或自身免疫中慢性免疫抑制的需要。在这项研究中，我们比较了地塞米松（Dex）和 1α，25-二羟维生素 D3（VD3）调节的 DC 的耐受能力。用 VD3 或 Dex 处理单核细胞会导致 DC 具有稳定的、半成熟的表型，与标准 DC 相比，共刺激和 MHC Ⅱ类分子的水平中等，在随后的促炎刺激后仍保持不变。VD3-DC 和 Dex-DC 均失去了 IL-12p70 的分泌，而 IL-10 的分泌不受影响。VD3-DC 明显产生大量的 TNF-α。VD3-DC 和 Dex-DC 均具有将 CD4 T 细胞转化为强有力地抑制应答 T 细胞增殖的 IL-10 分泌 Treg 的能力。然而，只有由 VD3-DC 诱导的 Treg 表现出抗原特异性。VD3-DC 在激活时表达高水平的程序性死亡配体 1（PD-L1），而 Dex-DC 则没有。在启动时阻断 PD-L1 会促使 T 细胞转而产生 IFN-γ而不是 IL-10，并消除获得调节能力。我们的研究结果表明，VD3-DC 和 Dex-DC 均具有持久但不同的耐受特征，通过不同的机制发挥作用。两者都有可能用于特异性下调不必要的免疫反应并诱导免疫耐受。这些调节性 DC 似乎适合作为抗原特异性临床疫苗接种干预策略的佐剂。
