Division of Immune Receptors and T Cell Activation, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
PLoS Pathog. 2013 Mar;9(3):e1003253. doi: 10.1371/journal.ppat.1003253. Epub 2013 Mar 21.
T cell immunoglobulin and mucin protein 3 (TIM-3) is a type I cell surface protein that was originally identified as a marker for murine T helper type 1 cells. TIM-3 was found to negatively regulate murine T cell responses and galectin-9 was described as a binding partner that mediates T cell inhibitory effects of TIM-3. Moreover, it was reported that like PD-1 the classical exhaustion marker, TIM-3 is up-regulated in exhausted murine and human T cells and TIM-3 blockade was described to restore the function of these T cells. Here we show that the activation of human T cells is not affected by the presence of galectin-9 or antibodies to TIM-3. Furthermore, extensive studies on the interaction of galectin-9 with human and murine TIM-3 did not yield evidence for specific binding between these molecules. Moreover, profound differences were observed when analysing the expression of TIM-3 and PD-1 on T cells of HIV-1-infected individuals: TIM-3 was expressed on fewer cells and also at much lower levels. Furthermore, whereas PD-1 was preferentially expressed on CD45RA(-)CD8 T cells, the majority of TIM-3-expressing CD8 T cells were CD45RA(+). Importantly, we found that TIM-3 antibodies were ineffective in increasing anti-HIV-1 T cell responses in vitro, whereas PD-L antibodies potently reverted the dysfunctional state of exhausted CD8 T cells. Taken together, our results are not in support of an interaction between TIM-3 and galectin-9 and yield no evidence for a functional role of TIM-3 in human T cell activation. Moreover, our data indicate that PD-1, but not TIM-3, is a promising target to ameliorate T cell exhaustion.
T 细胞免疫球蛋白和粘蛋白 3（TIM-3）是一种 I 型细胞表面蛋白，最初被鉴定为小鼠辅助性 T 细胞 1 的标志物。TIM-3 被发现负调控小鼠 T 细胞反应，半乳糖凝集素-9 被描述为介导 TIM-3 抑制 T 细胞作用的结合伴侣。此外，据报道，与经典衰竭标志物 PD-1 一样，TIM-3 在衰竭的小鼠和人类 T 细胞中上调，并且 TIM-3 阻断被描述为恢复这些 T 细胞的功能。在这里，我们表明人类 T 细胞的激活不受半乳糖凝集素-9 或 TIM-3 抗体的存在影响。此外，对半乳糖凝集素-9 与人类和小鼠 TIM-3 相互作用的广泛研究没有提供这些分子之间特异性结合的证据。此外，在分析 HIV-1 感染个体 T 细胞中 TIM-3 和 PD-1 的表达时观察到深刻的差异：TIM-3 的表达细胞较少，水平也低得多。此外，虽然 PD-1 优先表达在 CD45RA(-)CD8 T 细胞上，但大多数表达 TIM-3 的 CD8 T 细胞是 CD45RA(+)。重要的是，我们发现 TIM-3 抗体在体外不能增加抗 HIV-1 T 细胞反应，而 PD-L 抗体则有效地逆转了衰竭的 CD8 T 细胞的功能障碍状态。总之，我们的结果不支持 TIM-3 和半乳糖凝集素-9 之间的相互作用，也没有证据表明 TIM-3 在人类 T 细胞激活中具有功能作用。此外，我们的数据表明 PD-1 而不是 TIM-3 是改善 T 细胞衰竭的有前途的靶点。
