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

Xueping Yu (), Feifei Yang, Zhongliang Shen, Yao Zhang, Jian Sun, Chao Qiu, Yijuan Zheng, Weidong Zhao, Songhua Yuan, Dawu Zeng, Shenyan Zhang, Jianfei Long, Mengqi Zhu, Xueyun Zhang, Jingwen Wu, Zhenxuan Ma, Haoxiang Zhu, Milong Su, Jianqing Xu, Bin Li, Richeng Mao (), Zhijun Su () and Jiming Zhang ()
Additional contact information
Xueping Yu: Fudan University
Feifei Yang: Fudan University
Zhongliang Shen: Fudan University
Yao Zhang: Fudan University
Jian Sun: Fudan University
Chao Qiu: Fudan University
Yijuan Zheng: First Hospital of Quanzhou Affiliated to Fujian Medical University
Weidong Zhao: Dali University
Songhua Yuan: Fudan University
Dawu Zeng: Fujian Medical University
Shenyan Zhang: Fudan University
Jianfei Long: Fudan University
Mengqi Zhu: Fudan University
Xueyun Zhang: Fudan University
Jingwen Wu: Fudan University
Zhenxuan Ma: Fudan University
Haoxiang Zhu: Fudan University
Milong Su: First Hospital of Quanzhou Affiliated to Fujian Medical University
Jianqing Xu: Fudan University
Bin Li: Shanghai JiaoTong University School of Medicine
Richeng Mao: Fudan University
Zhijun Su: First Hospital of Quanzhou Affiliated to Fujian Medical University
Jiming Zhang: Fudan University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-46047-8

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