Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, Düsseldorf, Germany.
PLoS One. 2010 Dec 16;5(12):e15567. doi: 10.1371/journal.pone.0015567.
Production of type I interferons, consisting mainly of multiple IFNα subtypes and IFNβ, represents an essential part of the innate immune defense against invading pathogens. While in most situations, namely viral infections, this class of cytokines is indispensable for host survival they mediate a detrimental effect during infection with L. monocytogenes by rendering macrophages insensitive towards IFNγ signalling which leads to a lethal bacterial pathology in mice. Due to a lack of suitable analytic tools the precise identity of the cell population responsible for type I IFN production remains ill-defined and so far these cells have been described to be macrophages. As in general IFNβ is the first type I interferon to be produced, we took advantage of an IFNβ fluorescence reporter-knockin mouse model in which YFP is expressed from a bicistronic mRNA linked by an IRES to the endogenous ifnb mRNA to assess the IFNβ production on a single cell level in situ. Our results showed highest frequencies and absolute numbers of IFNβ+ cells in the spleen 24 h after infection with L. monocytogenes where they were located predominately in the white pulp within the foci of infection. Detailed FACS surface marker analyses, intracellular cytokine stainings and T cell proliferation assays revealed that the IFNβ+ cells were a phenotypically and functionally further specialized subpopulation of TNF and iNOS producing DCs (Tip-DCs) which are known to be essential for the early containment of L. monocytogenes infection. We proved that the IFNβ+ cells exhibited the hallmark characteristics of Tip-DCs as they produced iNOS and TNF and possessed T cell priming abilities. These results point to a yet unappreciated ambiguous role for a multi-effector, IFNβ producing subpopulation of Tip-DCs in controlling the balance between containment of L. monocytogenes infection and effects detrimental to the host driven by IFNβ.
I 型干扰素的产生主要由多种 IFNα 亚型和 IFNβ 组成，是宿主抵御入侵病原体的固有免疫防御的重要组成部分。虽然在大多数情况下，即病毒感染时，这类细胞因子对宿主的生存是不可或缺的，但它们在感染李斯特菌时会产生有害影响，使巨噬细胞对 IFNγ 信号不敏感，从而导致小鼠致命的细菌病理学。由于缺乏合适的分析工具，负责产生 I 型干扰素的细胞群体的确切身份仍未确定，到目前为止，这些细胞被描述为巨噬细胞。由于 IFNβ 通常是第一种产生的 I 型干扰素，我们利用 IFNβ 荧光报告基因敲入小鼠模型，其中 YFP 由连接到内源性 ifnb mRNA 的 IRES 的双顺反子 mRNA 表达，以在体内原位评估单个细胞水平的 IFNβ 产生。我们的结果显示，在感染李斯特菌 24 小时后，脾脏中 IFNβ+细胞的频率和绝对数量最高，它们主要位于感染灶内的白髓中。详细的 FACS 表面标记分析、细胞内细胞因子染色和 T 细胞增殖测定表明，IFNβ+细胞是 TNF 和 iNOS 产生 DC（Tip-DC）的一种表型和功能进一步特化的亚群，已知它们对早期控制李斯特菌感染至关重要。我们证明，IFNβ+细胞表现出 Tip-DC 的标志性特征，因为它们产生 iNOS 和 TNF 并具有 T 细胞启动能力。这些结果表明，在控制李斯特菌感染的控制和 IFNβ 驱动的对宿主有害影响之间的平衡方面，Tip-DC 的多效性、IFNβ 产生亚群起着尚未被认识的模糊作用。
