Golden-Mason Lucy, Waasdorp Hurtado Christine E, Cheng Linling, Rosen Hugo R
Division of Gastroenterology and Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver (UCD), Aurora, CO 80045, USA.
Pediatric Gastroenterology, Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, USA.
Clin Immunol. 2015 May;158(1):114-25. doi: 10.1016/j.clim.2015.03.008. Epub 2015 Mar 19.
T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) is an inhibitory receptor implicated in T cell exhaustion characteristic of chronic viral infection. Limited data exist on NK cell Tim-3 expression and functional consequences. In chronic hepatitis C virus (HCV)-infected subjects, we found increased Tim-3 on NKs, which was associated with an activated phenotype. The high level of Tim-3 was not reversed by successful IFN-alpha-based antiviral therapy. Tim-3(high) NK cells up-regulated TRAIL in response to IFN-alpha to a greater extent and demonstrated greater lymphokine-activated killing activity, viral control, and degranulation but similar cytokine production than their Tim-3(low) counterparts. Our results suggest that Tim-3 on NKs is associated with activation of this innate lymphocyte population that is polarized towards cytotoxicity in chronic HCV. These findings reveal roles for Tim-3 in the regulation of NKs that might represent targets for treatment of chronic viral infections.
含T细胞免疫球蛋白和粘蛋白结构域分子3（Tim-3）是一种抑制性受体，与慢性病毒感染所特有的T细胞耗竭有关。关于自然杀伤细胞（NK细胞）Tim-3表达及其功能后果的数据有限。在慢性丙型肝炎病毒（HCV）感染的受试者中，我们发现NK细胞上的Tim-3增加，这与一种活化表型相关。基于干扰素-α的成功抗病毒治疗并未使Tim-3的高水平恢复正常。与Tim-3低表达的NK细胞相比，Tim-3高表达的NK细胞对干扰素-α的反应能更大程度地上调肿瘤坏死因子相关凋亡诱导配体（TRAIL），并表现出更强的淋巴因子激活的杀伤活性、病毒控制能力和脱颗粒能力，但细胞因子产生情况相似。我们的结果表明，NK细胞上的Tim-3与这种先天性淋巴细胞群体的活化有关，该群体在慢性HCV感染中向细胞毒性极化。这些发现揭示了Tim-3在NK细胞调节中的作用，这可能代表了慢性病毒感染治疗的靶点。
