Institute of Beijing Brain Sciences, Beijing, China.
Wenzhou Medical University, Wenzhou, China.
Scand J Immunol. 2019 Feb;89(2):e12738. doi: 10.1111/sji.12738. Epub 2019 Jan 4.
T cell immunoglobulin and mucin domain protein 3 (Tim-3) is an immune checkpoint inhibitor in T cells and innate immune cells. The deregulated upregulation of Tim-3 is related to immune exhaustion in tumour and viral infection. To overcome Tim-3-mediated immune tolerance, we developed a novel monoclonal antibody against human Tim-3 (L3G) and investigated its roles in inhibiting Tim-3 signalling and overcoming immune tolerance in T cells and monocytes/macrophages. The administration of L3G to cultured peripheral blood mononuclear cells (PBMCs) significantly increased the production of IFN-γ and IL-2 and the expression of type I interferon. The administration of L3G also increased the production of IFN-γ, IL-8 and type I interferon in U937 cells and primary monocytes. We investigated the mechanisms by which L3G enhances pro-inflammatory cytokine expression, and our data show that L3G enhances STAT1 phosphorylation in both monocytes/macrophages and T cells. Finally, in an H1N1 infection model of PBMCs and U937 cells, L3G decreased the viral load and enhanced the expression of interferon. Thus, we developed a functional antibody with therapeutic potential against Tim-3-mediated infection tolerance.
T 细胞免疫球蛋白和黏蛋白结构域蛋白 3（Tim-3）是 T 细胞和固有免疫细胞中的一种免疫检查点抑制剂。Tim-3 的失调上调与肿瘤和病毒感染中的免疫衰竭有关。为了克服 Tim-3 介导的免疫耐受，我们开发了一种针对人 Tim-3（L3G）的新型单克隆抗体，并研究了其在抑制 T 细胞和单核细胞/巨噬细胞中的 Tim-3 信号传导和克服免疫耐受中的作用。L3G 给药至培养的外周血单核细胞（PBMC）中显著增加 IFN-γ 和 IL-2 的产生和 I 型干扰素的表达。L3G 给药还增加了 U937 细胞和原代单核细胞中 IFN-γ、IL-8 和 I 型干扰素的产生。我们研究了 L3G 增强促炎细胞因子表达的机制，我们的数据表明 L3G 增强了单核细胞/巨噬细胞和 T 细胞中 STAT1 的磷酸化。最后，在 PBMC 和 U937 细胞的 H1N1 感染模型中，L3G 降低了病毒载量并增强了干扰素的表达。因此，我们开发了一种具有针对 Tim-3 介导的感染耐受的治疗潜力的功能性抗体。
