Background. B7 family members and ligands have been identified as critical checkpoints in orchestrating the immune response during sepsis. V-domain Ig suppressor of T cell activation (VISTA) is a new inhibitory immune checkpoint involved in restraining T cell response. Previous studies demonstrated that VISTA engagement on T cells and myeloid cells could transmit inhibitory signals, resulting in reduced activation and function. The current study was designed to determine the potential therapeutic effects of a high-affinity anti-VISTA antibody (clone MH5A) in a murine model of sepsis. Methods. Polymicrobial sepsis was induced in male C57BL/6 mice via cecal ligation and puncture. Expression profiles of VISTA on T lymphocytes and macrophage were examined at 24 and 72 h postsurgery. The effects of anti-VISTA mAb on the 7-day survival, lymphocyte apoptosis, cytokine expression, bacterial burden, and vital organ damage were determined. Furthermore, the effects of anti-VISTA mAb on CD3⁺ T cell apoptosis and macrophage activation were determined in vitro. Results. VISTA was substantially expressed on T cells and macrophages in sham-operated mice; septic peritonitis did not induce significant changes in the expression profiles. Treatment with MH5A improved the survival of septic mice, accompanied by reduced lymphocyte apoptosis, decreased cytokine expression, and enhanced bacterial clearance. Engagement of VISTA receptor with MH5A mitigated CD3⁺ T cell apoptosis cultured from CLP mice and suppressed LPS-induced cytokine production by macrophage in vitro. Conclusion. The present study identified VISTA as a novel immune checkpoint in the regulation of T cell and macrophage response during sepsis. Modulation of the VISTA pathway might offer a promising opportunity in the immunotherapy for sepsis.

中文翻译：

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高亲和力抗 VISTA 抗体通过抑制 T 淋巴细胞凋亡和抑制炎症反应来预防脓毒症

背景。B7 家族成员和配体已被确定为在脓毒症期间协调免疫反应的关键检查点。T 细胞活化的 V 域 Ig 抑制因子 (VISTA) 是一种新的抑制性免疫检查点，参与抑制 T 细胞反应。先前的研究表明，VISTA 对 T 细胞和骨髓细胞的参与可以传递抑制信号，从而导致激活和功能降低。目前的研究旨在确定高亲和力抗 VISTA 抗体（克隆 MH5A）在败血症小鼠模型中的潜在治疗效果。方法. 通过盲肠结扎和穿刺在雄性 C57BL/6 小鼠中诱导多种微生物败血症。在术后 24 和 72 小时检查 VISTA 在 T 淋巴细胞和巨噬细胞上的表达谱。确定了抗 VISTA mAb 对 7 天存活率、淋巴细胞凋亡、细胞因子表达、细菌负荷和重要器官损伤的影响。此外，在体外测定了抗 VISTA mAb 对 CD3 ⁺ T 细胞凋亡和巨噬细胞活化的影响。结果. VISTA 在假手术小鼠的 T 细胞和巨噬细胞上大量表达；脓毒性腹膜炎没有引起表达谱的显着变化。MH5A 治疗可提高脓毒症小鼠的存活率，同时减少淋巴细胞凋亡、降低细胞因子表达和增强细菌清除率。VISTA 受体与 MH5A 的结合减轻了 CLP 小鼠培养的 CD3 ^{+ T 细胞凋亡，并}在体外抑制了 LPS 诱导的巨噬细胞产生的细胞因子。结论。本研究将 VISTA 确定为脓毒症期间调节 T 细胞和巨噬细胞反应的新型免疫检查点。VISTA 通路的调节可能为败血症的免疫治疗提供有希望的机会。