Type I interferons directly regulate lymphocyte recirculation and cause transient blood lymphopenia
Type I interferons directly regulate lymphocyte recirculation and cause transient blood lymphopenia
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DOI：
10.1182/blood-2006-06-027599
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发表时间：
2006-11-15
期刊：
影响因子：
20.3
通讯作者：
Kalinke, Ulrich
中科院分区：
文献类型：
--
作者：
Kamphuis, Elisabeth;Junt, Tobias;Kalinke, Ulrich
早期病毒感染通常与淋巴细胞减少症有关，淋巴细胞减少症是在临床症状出现之前很久血液淋巴细胞计数的短暂减少。我们研究了淋巴细胞减少症的小鼠感染水泡性口炎病毒（VSV）或治疗与Toll样受体（TLR）激动剂聚（I：C）和R-848。在分析的所有病例中，淋巴细胞减少症严重依赖于I型干扰素受体（IFNAR）信号传导。使用骨髓嵌合体小鼠，可以排除放射抗性细胞，如基质和内皮细胞作为诱导淋巴细胞减少症的I型干扰素（IFN-α/β）靶点。相反，在具有B或T细胞特异性IFNAR缺失的条件基因靶向小鼠中的过继转移实验和研究表明，IFN-α/β对淋巴细胞产生直接作用，这是诱导淋巴细胞减少症所必需的并且在很大程度上足以诱导淋巴细胞减少症。此外，在用R-848治疗后，我们发现其他细胞因子如TNF-α也在T细胞淋巴细胞减少症中发挥作用。分子机制的研究表明，淋巴细胞减少主要是独立的G蛋白偶联受体（GPCRs）和趋化因子。在粘附试验中，poly（I：C）处理的小鼠的B细胞显示对ICAM-1的粘附适度增加，但对VCAM-1没有。总之，我们的数据确定了一个新的影响，直接IFN-α/β刺激淋巴细胞，深刻影响淋巴细胞再分布。
Early viral infection is often associated with lymphopenia, a transient reduction of blood lymphocyte counts long before the onset of clinical symptoms. We have investigated lymphopenia in mice infected with vesicular stomatitis virus (VSV) or treated with the Toll-like receptor (TLR) agonists poly(I:C) and R-848. In all cases analyzed, lymphopenia was critically dependent on type I interferon receptor (IFNAR) signaling. With the use of bone marrow-chimeric mice, radioresistant cells, such as stroma and endothelium, could be excluded as type I interferon (IFN-alpha/p) targets for the induction of lymphopenia. Instead, adoptive transfer experiments and studies in conditionally gene-targeted mice with a B- or T-cell-specific IFNAR deletion demonstrated that IFN-alpha/beta exerted a direct effect on lymphocytes that was necessary and largely sufficient to induce lymphopenia. Furthermore, after treatment with R-848, we found that other cytokines such as TNF-alpha also played a role in T-cell lymphopenia. Investigation of the molecular mechanism revealed that lymphopenia was mainly independent of G protein-coupled receptors (GPCRs) and chemokines. In an adhesion assay, B cells of poly(I:C)-treated mice showed moderately increased adhesion to ICAM-1 but not to VCAM-1. In conclusion, our data identify a new effect of direct IFN-alpha/beta stimulation of lymphocytes that profoundly affects lymphocyte redistribution.