Abstract：
Familial forms of hemophagocytic lymphohistiocytosis (HLH) are caused by loss-of-function mutations in genes encoding perforin as well as those required for release of perforin-containing cytotoxic granule constituent. Perforin is expressed by subsets of CD8+ T cells and NK cells, representing lymphocytes that share mechanism of target cell killing yet display distinct modes of target cell recognition. Here, we highlight recent findings concerning the genetics of familial HLH that implicate CD8+ T cells in the pathogenesis of HLH and discuss mechanistic insights from animal models as well as patients that reveal how CD8+ T cells may contribute to or drive disease, at least in part through release of IFN-γ. Intriguingly, CD8+ T cells and NK cells may act differentially in severe hyperinflammatory diseases such as HLH. We also discuss how CD8+ T cells may promote or drive pathology in other cytokine release syndromes (CSS). Moreover, we review the molecular mechanisms underpinning CD8+ T cell-mediated lymphocyte cytotoxicity, key to the development of familial HLH. Together, recent insights to the pathophysiology of CSS in general and HLH in particular are providing promising new therapeutic targets.
摘要：
噬血细胞性淋巴组织细胞增生症（HLH）的家族形式是由编码穿孔素的基因中的功能丧失突变以及释放含穿孔素的细胞毒性颗粒成分所需的突变引起的。穿孔素由CD8+T细胞和NK细胞的亚群表达，代表共享靶细胞杀伤机制的淋巴细胞，但显示出不同的靶细胞识别模式。这里,我们重点介绍了有关家族性HLH遗传学的最新发现，这些发现涉及CD8+T细胞在HLH发病机理中的作用，并讨论了动物模型和患者的机制见解，揭示了CD8+T细胞如何促进或驱动疾病。至少部分地通过IFN-γ的释放。有趣的是，CD8+T细胞和NK细胞可能在严重的高炎性疾病如HLH中不同地发挥作用。我们还讨论了CD8+T细胞如何促进或驱动其他细胞因子释放综合征（CSS）的病理。此外，我们综述了CD8+T细胞介导的淋巴细胞毒性的分子机制，家族性HLH发展的关键。一起,对CSS的病理生理学的最新见解，尤其是HLH正在提供有希望的新治疗靶点。
