Frazer Institute, Faculty of Medicine, The University of Queensland, Woolloongabba, QLD, Australia.
Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, QLD, Australia.
Immunol Cell Biol. 2024 Sep;102(8):721-733. doi: 10.1111/imcb.12794. Epub 2024 Jun 14.
Antibiotic resistance is a major public health threat, and alternatives to antibiotic therapy are urgently needed. Immunotherapy, particularly the blockade of inhibitory immune checkpoints, is a leading treatment option in cancer and autoimmunity. In this study, we used a murine model of Salmonella Typhimurium infection to investigate whether immune checkpoint blockade could be applied to bacterial infection. We found that the immune checkpoint T-cell immunoglobulin and ITIM domain (TIGIT) was significantly upregulated on lymphocytes during infection, particularly on CD4 T cells, drastically limiting their proinflammatory function. Blockade of TIGIT in vivo using monoclonal antibodies was able to enhance immunity and improve bacterial clearance. The efficacy of anti-TIGIT was dependent on the capacity of the antibody to bind to Fc (fragment crystallizable) receptors, giving important insights into the mechanism of anti-TIGIT therapy. This research suggests that targeting immune checkpoints, such as TIGIT, has the potential to enhance immune responses toward bacteria and restore antibacterial treatment options in the face of antibiotic resistance.
抗生素耐药性是一个主要的公共卫生威胁，迫切需要替代抗生素治疗的方法。免疫疗法，特别是抑制性免疫检查点的阻断，是癌症和自身免疫疾病的主要治疗选择。在这项研究中，我们使用了鼠伤寒沙门氏菌感染的小鼠模型来研究免疫检查点阻断是否可应用于细菌感染。我们发现，在感染过程中，淋巴细胞特别是 CD4 T 细胞上的 T 细胞免疫球蛋白和 ITIM 结构域（TIGIT）显著上调，极大地限制了它们的促炎功能。使用单克隆抗体在体内阻断 TIGIT 能够增强免疫力并改善细菌清除。抗 TIGIT 的疗效取决于抗体与 Fc（片段结晶）受体结合的能力，这为抗 TIGIT 治疗的机制提供了重要的见解。这项研究表明，靶向免疫检查点（如 TIGIT）有可能增强针对细菌的免疫反应，并在面临抗生素耐药性的情况下恢复抗菌治疗选择。
