Sustained high expression of BTLA on CD4+ T cell contributes to high rate of bacterial infection and mortality in patients with HBV-related acute-on-chronic liver failure via CD4+ T cell exhaustion
crossref(2022)
Abstract
Abstract Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is characterized by susceptibility to infection and T-cell immune exhaustion. Moreover, expression of the B- and T-lymphocyte attenuator (BTLA), which maintains T-cell immune tolerance, increases in HBV-ACLF patients. However, the mechanisms underlying BTLA expansion in HBV-ACLF patients, and whether BTLA can induce T-cell immune exhaustion and increase the risk of infection remain unclear. Here, we demonstrate that BTLA expression was significantly increased in the T effector memory subtype and all subgroups of circulating and intrahepatic CD4+T cells from patients with HBV-ACLF. The prevalence of BTLA+CD4+T cells was positively correlated with disease severity, prognosis, and infectious complications. BTLA expression was upregulated by the IL-6 and TNF-α signaling pathways, but blocked by their inhibitors. Crosslinking of BTLA phosphorylated the SHP1/2 protein and activated the PI3K-Akt-GSK-3β pathway to inhibit the activation, proliferation, and cytokine production of CD4+T cells while promoting their apoptosis; contrastingly, BTLA knockdown promoted their activation and proliferation. BTLA−/− ACLF mice showed increased secretion of cytokines, CD4+T-cell activation, and reduced mortality and bacterial burden. Together, these data will be helpful for elucidating the pathogenesis of HBV-ACLF and in the identification of new drug targets.
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