Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, 200040, Shanghai, China.
Department of Infectious Diseases, First Hospital of Quanzhou Affiliated to Fujian Medical University, 362000, Quanzhou, China.
Nat Commun. 2024 Feb 28;15(1):1835. doi: 10.1038/s41467-024-46047-8.
B- and T-lymphocyte attenuator (BTLA) levels are increased in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). This condition is characterized by susceptibility to infection and T-cell immune exhaustion. However, whether BTLA can induce T-cell immune exhaustion and increase the risk of infection remains unclear. Here, we report that BTLA levels are significantly increased in the circulating and intrahepatic CD4 T cells from patients with HBV-ACLF, and are positively correlated with disease severity, prognosis, and infection complications. BTLA levels were upregulated by the IL-6 and TNF signaling pathways. Antibody crosslinking of BTLA activated the PI3K-Akt pathway to inhibit the activation, proliferation, and cytokine production of CD4 T cells while promoting their apoptosis. In contrast, BTLA knockdown promoted their activation and proliferation. BTLA ACLF mice exhibited increased cytokine secretion, and reduced mortality and bacterial burden. The administration of a neutralizing anti-BTLA antibody reduced Klebsiella pneumoniae load and mortality in mice with ACLF. These data may help elucidate HBV-ACLF pathogenesis and aid in identifying novel drug targets.
B 细胞和 T 细胞衰减因子（BTLA）水平在乙型肝炎病毒相关慢加急性肝衰竭（HBV-ACLF）患者中升高。这种情况的特征是易感染和 T 细胞免疫衰竭。然而，BTLA 是否会诱导 T 细胞免疫衰竭并增加感染风险尚不清楚。在这里，我们报告说，HBV-ACLF 患者循环和肝内 CD4 T 细胞中的 BTLA 水平显著升高，与疾病严重程度、预后和感染并发症呈正相关。BTLA 水平受 IL-6 和 TNF 信号通路上调。BTLA 的抗体交联激活了 PI3K-Akt 通路，抑制 CD4 T 细胞的激活、增殖和细胞因子产生，同时促进其凋亡。相比之下，BTLA 的敲低促进了它们的激活和增殖。BTLA ACLF 小鼠表现出细胞因子分泌增加，死亡率和细菌负荷降低。在 ACLF 小鼠中，中和性抗 BTLA 抗体的给药可降低肺炎克雷伯菌负荷和死亡率。这些数据可能有助于阐明 HBV-ACLF 的发病机制，并有助于确定新的药物靶点。
