C-C chemokine receptor type 7 (CCR7) regulates hepatic CD8+ T cell homeostasis and response to acute liver injury - Nanostring gene expression data

Acute liver failure (ALF) is a rare but life-threatening condition, and drug-induced liver injury (DILI), particularly acetaminophen (APAP) toxicity, is the leading cause of ALF. Innate immune mechanisms further perpetuate liver injury, while the role of the adaptive immune system in DILI-related ALF is unclear. We analyzed liver tissue from two independent patient cohorts with ALF and identified hepatic T cell infiltration as a prominent feature in human ALF. CD8+ T cells were characterised by zonation towards necrotic regions and an activated gene expression signature. In murine APAP-induced liver injury, intravital microscopy revealed zonation of CD8+ but not CD4+ T cells at necrotic areas. Gene expression analysis exposed pregulated C-C chemokine receptor 7 (CCR7) and its ligand CCL21 in liver as well as a broadly activated phenotype of hepatic CD8+ T cells. In two mouse models of ALF, Ccr7-/- mice had significantly aggravated early-phase liver damage. Functionally, CCR7 was not involved in the recruitment of CD8+ T cells, but regulated their activation profile potentially via egress to lymphatics. Ccr7-/- CD8+ T cells were characterized by elevated expression of activation, effector, and exhaustion profiles. In this data set, gene expression of sorted CD4+ or CD8+ T-cells from liver leukocyte extracts of either WT or CCR7-knock-out mice that were either untreated or challenged with APAP was measured using the nCounter Mouse Immunology Kit.急性肝衰竭（Acute liver failure, ALF）是一种罕见但危及生命的重症病症，药物性肝损伤（drug-induced liver injury, DILI）尤以对乙酰氨基酚（acetaminophen, APAP）中毒最为突出，是ALF的首要致病原因。固有免疫机制可进一步加剧肝损伤，而适应性免疫系统在DILI相关性ALF中的作用仍未明确。本研究对两个独立的ALF患者队列的肝组织进行分析，发现肝T细胞浸润是人类ALF的显著特征。CD8+ T细胞呈现出向坏死区域的分区分布特征，并具备激活型基因表达谱。在APAP诱导的小鼠肝损伤模型中，活体显微镜成像显示CD8+ T细胞而非CD4+ T细胞在坏死区域呈现分区分布。基因表达分析结果显示，肝脏内C-C趋化因子受体7（C-C chemokine receptor 7, CCR7）及其配体CCL21呈预上调状态，同时肝内CD8+ T细胞呈现广泛激活的表型。在两种ALF小鼠模型中，Ccr7基因敲除（Ccr7-/-）小鼠的早期肝损伤程度显著加重。功能实验表明，CCR7并未参与CD8+ T细胞的招募过程，而是可能通过调控其向淋巴管的迁出，进而调节CD8+ T细胞的激活状态。Ccr7-/- CD8+ T细胞的特征为激活、效应及耗竭相关基因的表达水平显著升高。 本数据集采用nCounter小鼠免疫试剂盒（nCounter Mouse Immunology Kit），对未处理或经APAP造模的野生型（wild type, WT）或CCR7基因敲除小鼠的肝白细胞提取物中分选得到的CD4+或CD8+ T细胞的基因表达水平进行了检测。