Btla, also known as B and T lymphocyte attenuator, is one of the most important cosignaling molecules in the CD28 superfamily, similar to PD-1 and CTLA-4 in structure and function [2]. It is mainly expressed on B, T, and all mature lymphocyte cells [5]. BTLA can induce immunosuppression by inhibiting B and T cell activation and proliferation [2]. Its ligand, HVEM (herpesvirus entry mediator), belongs to the tumor necrosis factor receptor (TNFR) superfamily, and the association of BTLA with HVEM bridges the CD28 and TNFR families, mediating broad immune effects [2]. BTLA is crucial for maintaining immunological self-tolerance and preventing autoimmune diseases [3].

In the context of cancer, high BTLA expression in chimeric antigen receptor (CAR) T cells correlated with poor clinical response to treatment. Deleting BTLA in CAR T cells improved tumor control and persistence in lymphoma and solid malignancy models. Mechanistically, BTLA inhibits CAR T cells via recruitment of tyrosine phosphatases SHP-1 and SHP-2 upon trans-engagement with HVEM, and BTLA knockout promotes CAR signaling and enhances effector function [1]. In acute-on-chronic liver failure related to hepatitis B virus, BTLA levels were increased in circulating and intrahepatic CD4+ T cells. Antibody cross-linking of BTLA inhibited CD4+ T cell activation, proliferation, and cytokine production, while promoting apoptosis. BTLA -/- ACLF mice had increased cytokine secretion, reduced mortality, and bacterial burden [4].

In summary, BTLA plays a key role in immunosuppression, and its interaction with HVEM is important for immune regulation. Gene knockout studies in mouse models have revealed its negative impact on anti-tumor immunity in cancer and its role in the pathogenesis of acute-on-chronic liver failure, providing potential therapeutic targets for these diseases.

References:

1. Guruprasad, Puneeth, Carturan, Alberto, Zhang, Yunlin, Porazzi, Patrizia, Ruella, Marco. 2024. The BTLA-HVEM axis restricts CAR T cell efficacy in cancer. In Nature immunology, 25, 1020-1032. doi:10.1038/s41590-024-01847-4. https://pubmed.ncbi.nlm.nih.gov/38831106/

2. Ning, Zhaochen, Liu, Keyan, Xiong, Huabao. 2021. Roles of BTLA in Immunity and Immune Disorders. In Frontiers in immunology, 12, 654960. doi:10.3389/fimmu.2021.654960. https://pubmed.ncbi.nlm.nih.gov/33859648/

3. Mohamed, Asma'a H, Obeid, Ruaa Ali, Fadhil, Ali Abdulhussain, Ahmad, Irfan, Alshahrani, Mohammad Y. 2023. BTLA and HVEM: Emerging players in the tumor microenvironment and cancer progression. In Cytokine, 172, 156412. doi:10.1016/j.cyto.2023.156412. https://pubmed.ncbi.nlm.nih.gov/39492110/

4. Yu, Xueping, Yang, Feifei, Shen, Zhongliang, Su, Zhijun, Zhang, Jiming. 2024. BTLA contributes to acute-on-chronic liver failure infection and mortality through CD4+ T-cell exhaustion. In Nature communications, 15, 1835. doi:10.1038/s41467-024-46047-8. https://pubmed.ncbi.nlm.nih.gov/38418488/

5. Yu, Xueping, Zheng, Yijuan, Mao, Richeng, Su, Zhijun, Zhang, Jiming. 2019. BTLA/HVEM Signaling: Milestones in Research and Role in Chronic Hepatitis B Virus Infection. In Frontiers in immunology, 10, 617. doi:10.3389/fimmu.2019.00617. https://pubmed.ncbi.nlm.nih.gov/30984188/