Luft Thomas, Luetjens Petra, Hochrein Hubertus, Toy Tracey, Masterman Kelly-Anne, Rizkalla Mark, Maliszewski Charlie, Shortman Ken, Cebon Jonathan, Maraskovsky Eugene
Melbourne Tumour Biology Branch, Ludwig Institute for Cancer Research, Austin and Repatriation Medical Centre, Heidelberg, Victoria 3084, Australia.
Int Immunol. 2002 Apr;14(4):367-80. doi: 10.1093/intimm/14.4.367.
Type I IFN are immune modulatory cytokines that are secreted during early stages of infection. Type I IFN bridge the innate and the adaptive immune system in humans and mice. We compared the capacity of type I and II IFN to induce the functional maturation of monocyte-derived dendritic cells (MoDC). Extending our earlier observation that type I IFN promote DC maturation, we report that these cytokines also enhance DC differentiation by augmenting CD40 ligand (CD40L)-induced cytokine secretion by MoDC. Type I IFN alone were poor inducers of MoDC maturation as compared with other stimuli. They up-regulated the expression of HLA-DR, CD80, CD86, partially CCR7 but not CD83, partially reduced antigen-uptake function, increased the levels of IL-12p35 mRNA, and prolonged surface expression of peptide-MHC class I complexes for presentation to cytotoxic T lymphocytes, but did not induce migration towards CCL21 chemokine. However, type I IFN were potent co-factors for CD40L-mediated function. Here, they enhanced CD40L-mediated IL-6, IL-10 and IL-12p70 secretion. Furthermore, when combined with IL-1beta and/or IL-4, IFN-alpha2a type I IFN increased CD40L-mediated IL-12p70 production by 2- to 3-fold, and biased the IL-12 p40/p70 ratio towards the IFN-gamma inducing p70 heterodimer, this correlating with higher levels of IFN-gamma secretion by allogeneic T cell subsets and NK cells. Our results suggest that the rapid expression of CD40L, IFN and IL-1beta at sites of infection and inflammation can act in concert on immature DC, thereby linking innate and adaptive immune responses. In this way, type I IFN play a dual role as DC maturation factors and enhancers of CD40L-mediated DC activation.
I型干扰素是在感染早期分泌的免疫调节细胞因子。I型干扰素在人类和小鼠中连接先天免疫系统和适应性免疫系统。我们比较了I型和II型干扰素诱导单核细胞来源的树突状细胞（MoDC）功能成熟的能力。扩展我们之前关于I型干扰素促进DC成熟的观察结果，我们报告这些细胞因子还通过增强MoDC的CD40配体（CD40L）诱导的细胞因子分泌来促进DC分化。与其他刺激相比，单独的I型干扰素是MoDC成熟的弱诱导剂。它们上调了HLA-DR、CD80、CD86的表达，部分上调了CCR7但未上调CD83的表达，部分降低了抗原摄取功能，增加了IL-12p35 mRNA的水平，并延长了肽-MHC I类复合物的表面表达以呈递给细胞毒性T淋巴细胞，但未诱导向CCL21趋化因子的迁移。然而，I型干扰素是CD40L介导功能的有效辅助因子。在此，它们增强了CD40L介导的IL-6、IL-10和IL-12p70分泌。此外，当与IL-1β和/或IL-4联合使用时，I型干扰素α2a使CD40L介导的IL-12p70产生增加2至3倍，并使IL-12 p40/p70比值偏向于诱导IFN-γ的p70异二聚体，这与同种异体T细胞亚群和NK细胞更高水平的IFN-γ分泌相关。我们的结果表明，感染和炎症部位CD40L、干扰素和IL-1β的快速表达可以协同作用于未成熟DC，从而连接先天免疫和适应性免疫反应。通过这种方式，I型干扰素作为DC成熟因子和CD40L介导的DC激活增强剂发挥双重作用。
