Luft Thomas, Jefford Michael, Luetjens Petra, Hochrein Hubertus, Masterman Kelly-Anne, Maliszewski Charlie, Shortman Ken, Cebon Jonathan, Maraskovsky Eugene
Melbourne Tumor Biology Branch, Ludwig Institute for Cancer Research, Austin and Repatriation Medical Center, Heidelberg, Victoria, Australia.
J Immunol. 2002 Jan 15;168(2):713-22. doi: 10.4049/jimmunol.168.2.713.
CD40 ligand (CD40L) is a membrane-bound molecule expressed by activated T cells. CD40L potently induces dendritic cell (DC) maturation and IL-12p70 secretion and plays a critical role during T cell priming in the lymph nodes. IFN-gamma and IL-4 are required for CD40L-mediated cytokine secretion, suggesting that T cells are required for optimal CD40L activity. Because CD40L is rapidly up-regulated by non-T cells during inflammation, CD40 stimulation may also be important at the primary infection site. However, a role for T cells at the earliest stages of infection is unclear. The present study demonstrates that the innate immune cell-derived cytokine, IL-1beta, can increase CD40L-induced cytokine secretion by monocyte-derived DC, CD34(+)-derived DC, and peripheral blood DC independently of T cell-derived cytokines. Furthermore, IL-1beta is constitutively produced by monocyte-derived DC and monocytes, and is increased in response to intact Escherichia coli or CD40L, whereas neither CD34(+)-derived DC nor peripheral blood DC produce IL-1beta. Finally, DC activated with CD40L and IL-1beta induce higher levels of IFN-gamma secretion by T cells compared with DC activated with CD40L alone. Therefore, IL-1beta is the first non-T cell-derived cytokine identified that enhances CD40L-mediated activation of DC. The synergy between CD40L and IL-1beta highlights a potent, T cell-independent mechanism for DC activation during the earliest stages of inflammatory responses.
CD40配体（CD40L）是一种由活化T细胞表达的膜结合分子。CD40L能有效诱导树突状细胞（DC）成熟和IL-12p70分泌，并在淋巴结中T细胞启动过程中发挥关键作用。IFN-γ和IL-4是CD40L介导的细胞因子分泌所必需的，这表明T细胞对于最佳的CD40L活性是必需的。由于在炎症过程中非T细胞能迅速上调CD40L，CD40刺激在原发性感染部位可能也很重要。然而，T细胞在感染最早阶段的作用尚不清楚。本研究表明，先天性免疫细胞衍生的细胞因子IL-1β可独立于T细胞衍生的细胞因子，增加单核细胞衍生的DC、CD34(+)衍生的DC和外周血DC中CD40L诱导的细胞因子分泌。此外，IL-1β由单核细胞衍生的DC和单核细胞组成性产生，并在对完整大肠杆菌或CD40L的反应中增加，而CD34(+)衍生的DC和外周血DC均不产生IL-1β。最后，与单独用CD40L激活的DC相比，用CD40L和IL-1β激活的DC诱导T细胞分泌更高水平的IFN-γ。因此，IL-1β是首个被鉴定出的能增强CD40L介导的DC激活的非T细胞衍生细胞因子。CD40L与IL-1β之间的协同作用突出了炎症反应最早阶段DC激活的一种有效的、不依赖T细胞的机制。
