BTLA contributes to acute-on-chronic liver failure infection and mortality through CD4+ T-cell exhaustion

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 are upregulated by the IL-6 and TNF signaling pathways, and are abolished or partially weakened by IL-6 and TNF inhibitors. 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 ACLF mice. These data help elucidate HBV-ACLF pathogenesis and aid in identifying novel drug targets. Overall design: To explore the mechanisms by which BTLA induces CD4+ T-cell exhaustion in HBV-ACLF patients and to seek drug targets for recovering the function of CD4+ T cells, we analyzed gene expression profiles in PBMC from NC, CHB, and HBV-ACLF patients with or without BTLA Ab treatment through next-generation high-throughput RNA-Seq.