修回日期: 2013-03-29
接受日期: 2013-06-05
在线出版日期: 2013-08-08
T细胞免疫球蛋白黏蛋白(T cell immunoglobulin mucin domain containing molecules, Tim)-3是一种Ⅰ型细胞表面糖蛋白, 表达于多种固有及适应性免疫应答细胞表面. Tim-3作为Tim家族中参与T细胞免疫应答的首位成员, 他通过与配体半乳凝集素(galectin-9, Gal-9)及磷脂酰丝氨酸(PtdSer)相互作用, 介导细胞凋亡及清除凋亡细胞, 负性调控Th1/Th17细胞免疫应答, 参与自身免疫性疾病、过敏性疾病、病毒感染相关性疾病等多种疾病. 目前研究表明Tim-3与消化系统炎症疾病密切相关, 本文将就相关文献报道进行综述.
核心提示: Tim-3负性调控Th1/Th17细胞免疫应答, Tim-3与配体gal-9结合介导细胞凋亡, 两者及其相关调控因子表达异常参与消化系疾病的发生发展.
引文著录: 余婧, 谢勇. T细胞免疫球蛋白黏蛋白3与消化系炎症疾病的关系. 世界华人消化杂志 2013; 21(22): 2169-2175
Revised: March 29, 2013
Accepted: June 5, 2013
Published online: August 8, 2013
T cell immunoglobulin mucin domain-containing molecules (Tim)-3 is a type I cell membrane glycoprotein that is expressed on the surface of cells involved in innate and adaptive immunity. As the first discovered member of Tim family, Tim-3 participates in T cell-induced immune responses. By interacting with its ligands galectin-9 or PtdSer, Tim-3 induces cell apoptosis and clearance of apoptotic cells in autoimmune disorders, allergic diseases and virus infection-associated diseases. Tim-3 can act as a negative regulator of Th1/Th17 immune responses. Current research has shown that Tim-3 is involved in the pathogenesis of inflammatory diseases of the digestive system. Here we will review the progress in understanding the role of Tim-3 in the pathogenesis of inflammatory diseases of the digestive system.
- Citation: Yu J, Xie Y. Role of Tim-3 in pathogenesis of inflammatory diseases of the digestive system. Shijie Huaren Xiaohua Zazhi 2013; 21(22): 2169-2175
- URL: https://www.wjgnet.com/1009-3079/full/v21/i22/2169.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v21.i22.2169
T细胞免疫球蛋白黏蛋白家族(T cell immunoglobulin mucin domain containing molecules, Tim)最初于2001年由McIntire等[1]在鼠的气道高反应调控位点区(Tapr)被发现, 该家族包含8个成员, 定位于鼠染色体11B1.1上, 在人类染色体上已鉴定表达的Tim家族成员是Tim-1、Tim-3和Tim-4, 定位于染色体5q33.2. Tim家族与T细胞免疫应答密切相关, T细胞免疫球蛋白黏蛋白(T cell immunoglobulin mucin domain containing molecules, Tim)-3作为Tim家族中的重要一员, 大量研究显示Tim-3参与以T细胞应答异常为主的多种疾病. 目前研究表明Tim-3与消化系炎症疾病密切相关, 包括肝炎病毒及幽门螺杆菌(Helicobacter pylori, H. pylori)、炎症性肠病、食物过敏所致肠道炎症浸润等, 现将Tim-3与他们的关系综述如下.
1 Tim-3的生物学性能及配体
人Tim-3分子由301个氨基酸组成, 其基因长约23 kb[2], 与鼠Tim-3具有63%的同源性, 表达在终末分化的CD4+Th1, CD8+Tc1细胞及Th17表面[3-5]. 此外, Tim-3也表达在人固有免疫细胞上, 如树突状细胞[6]、自然杀伤细胞[7]、单核巨噬细胞表面[8]. Tim-3是一种Ⅰ型细胞表面糖蛋白, 他由信号肽、胞外免疫球蛋白结构域、黏蛋白结构域、跨膜结构域及胞质尾区组成[2]. 其免疫球蛋白晶体结构分析显示, 该结构域的4个保守半胱氨酸之间形成的2个独特袋状结构, 为Tim-3与其配体结合及发挥效应提供了作用位点[9]. 现已明确Tim-3负性调控Th1免疫应答, 他通过与配体半乳凝集素(galectin-9, Gal-9)相互作用介导细胞凋亡, 参与自身免疫性疾病[10]、过敏性疾病[11]、病毒感染相关性疾病等多种疾病[12]. 而在固有免疫应答中, Tim-3可与Toll样受体(toll-like receptor, TLR)协同作用启动固有免疫应答, 通过刺激巨噬细胞活化参与自身免疫性[13]及感染性疾病[14]. Tim-3在固有及适应性免疫应答中发挥不同作用的现象, 是与树突状细胞(dendritic cells, DC)和Th1细胞表面Tim-3胞内段去酪氨酸磷酸化形式不同相关[6].
Gal-9作为Tim-3的天然配体[15], 他是一种大小约36 kDa的S型凝集素, 属于半乳糖凝集素家族中的一员, 1997年首次从霍奇金淋巴瘤中克隆出来[16], 广泛分布在肝脏、小肠、脾脏、心脏、胸腺、骨骼肌等处[17], 表达于多种类型细胞表面. Th1细胞通过分泌干扰素(interferon-γ, IFN-γ)上调Gal-9的表达[18], 后者与Tim-3相互作用介导抑制性信号, 促进钙内流, 选择性诱导Th1细胞凋亡[15,18,19]. 此外, Gal-9可促进T细胞分化成调节性T(regulatory T cells, Treg)细胞, 抑制其分化成Th17细胞[20], 同时可与Tim-3相互作用诱导Th17细胞凋亡[21]. DeKruyff等[22]发现Tim-3与其另一个配体磷脂酰丝氨酸(PtdSer)之间具有高达50%的亲和力, 两者相互作用可介导凋亡细胞吞噬, 维持内环境稳定, 参与自身免疫调节及免疫耐受诱导[23].
2.1.1 Tim-3与病毒感染相关性肝病: 病毒持续感染以适应性免疫应答受损为特征, 尤以CD8+ T细胞功能受损明显[24], 而有效的病毒特异性CD8+ T细胞应答在病毒清除中起重要作用[25].
Wu等[26]研究发现, 慢性乙肝病毒(chronic hepatitis B, CHB)感染患者外周血CD4+和CD8+ T细胞表面高表达Tim-3, 其水平与传统肝脏损伤标志物丙氨酸转移酶(alanine transaminase, ALT), 门冬氨酸转移酶(aspartate transferase, AST), 总胆红素(total bilirubin, TB)和国际标准化比率(International Normalized Ratio, INR)呈正相关, 经有效抗病毒治疗Tim-3表达下调, 提示Tim-3过表达参与持续乙型肝炎病毒(hepatitis B virus, HBV)感染, Tim-3可作为评估肝脏损伤程度的一个有效指标. Tim-3+CD8+ T细胞数目与转录因子T-bet mRNA及细胞因子IFN-γ水平呈负相关, 与病毒载量无关, 故研究者推测Tim-3通过下调Th1/Tc1细胞应答, 负性调控宿主免疫系统, 最终导致HBV持续感染. 此外, 有研究显示自然杀伤(natural killer, NK)细胞表面上调的Tim-3可与Gal-9相互作用, 抑制NK细胞的免疫活性, 导致HBV持续感染[27]. Wu等[28]进一步研究发现, 封闭Tim-3信号通路可修复部分分泌、增殖功能受损的Tim-3+CD8+ T细胞, 提示Tim-3信号通路负性调控病毒特异性CD8+ T细胞介导的免疫应答, 推测细胞功能修复与否受细胞本身损伤程度及抑制分子如PD-1、CTLA-4和CD244等影响, 具体机制尚不清楚. 此外, 急性乙肝病毒(acute hepatitis B, AHB)感染患者外周血CD8+ T细胞表面Tim-3呈一过性上调, 其表达水平与肝损标志物、转录因子及细胞因子水平无明显相关[26], 提示Tim-3在AHB和CHB感染致病中发挥效应不同, 导致了HBV感染结局的多样性. 与CHB感染类似, Tim-3在丙型肝炎病毒(hepatitis C virus, HCV)特异性CD8+ T细胞表面呈高表达[29,30], 慢性HCV感染患者肝内PD-1+Tim-3+CD8+ T细胞占肝总CD8+ T细胞比例远高于正常人群[29], 而大部分Tim-3在缓解晚期才降至正常水平[30], 提示PD-1+TIM-3+CD8+ T细胞可作为慢性HCV感染的一种主要肝内细胞显型[30], 同时Tim-3表达水平可作为感染转归的一个预测指标. 虽然封闭PD-1/Tim-3均可改善HCV特异性CD8+ T细胞的增殖功能[29-31], 但只有封闭Tim-3才能杀死HCV感染肝细胞[30], 提示Tim-3和PD-1在T细胞功能衰竭介导的不同阶段发挥作用. Zhang等[32]研究推测, Tim-3/Gal-9与PD-1和细胞因子信号传导抑制因子-1(suppressor of cytokine signaling-1, SOCS-1)相互作用, 限制STAT-1磷酸化, 负性调控TLR介导的白介素(interleukin, IL)-12分泌, 使固有免疫应答失调, 进而诱导适应性Th1/Tc1功能失调, 最终导致HCV持续感染. 此外, Mengshol等[33]研究显示, HCV感染患者肝枯否细胞表面高表达Gal-9, Gal-9可通过活化caspase8途径诱导HCV特异性CD8+ T细胞凋亡.
肝细胞癌(hepatocellular carcinoma, HCC)与HBV及HCV感染密切相关[34]. Li等[35]采用流式细胞术检测150例临床确诊HCC患者的癌及癌旁组织发现, Tim-3主要表达在肿瘤浸润T细胞表面, Gal-9主要在HBV相关HCC的枯否细胞表面呈高表达, Tim-3/Gal-9相互作用可介导HBV相关HCC的T细胞衰竭. HBV阳性HCC患者Tim-3+ T细胞在T细胞中所占比例远高于HBV阴性HCC患者, 提示Tim-3表达水平在一定程度上与肿瘤微环境相关. 此外, Tim-3+ T细胞数与肿瘤大小呈正相关, 与患者生存期呈负相关, 提示Tim-3+细胞数可作为判断HCC患者生存预后的一个指标.
此外, Li等[36]对789例中国汉族人口Tim-3基因启动子区-1541C/T, -1516G/T, -882C/T, -574G/T及外显子3区进行基因分型发现, -1516G/T位点与HBV易感性及HBV相关HCC特性(肿瘤分级、淋巴细胞转移)相关. 另一项相关性分析显示-1516基因显型GT/TT可能参与HCC的发展及转归[37].
总之, Tim-3在病毒感染相关肝病的发展、转归中发挥重要作用. 虽然大量研究已证明, Tim-3负性调控Th免疫应答, 但病毒感染相关肝病中高表达Tim-3的功能衰竭CD8+ T细胞是否发生凋亡, 发生凋亡又跟何种因素相关, 目前尚不清楚, 仍有待于进一步研究.
2.1.2 Tim-3与自身免疫性肝炎: 自身免疫性肝炎(autoimmune hepatitis, AIH)是一种慢性进行性肝脏炎症性疾病. 他主要由CD4+ T细胞通过识别自身抗原介导免疫应答. AIH与Treg功能缺陷及CD4+ T细胞低应答相关[38,39]. Liberal等[39]研究发现, AIH患者外周血Tim-3+CD4+ T细胞和Gal-9+ Treg细胞较健康人群少, 疾病复发组Tim-3+细胞数较缓解组少, 提示Tim-3+与Gal-9+细胞数与AIH相关. Tim-3+ T细胞较Tim-3- T细胞而言, 前者对Treg细胞的负性调控作用更易感, 尤其是CD127-Treg细胞, 表明Tim-3参与CD4+ T细胞与Treg细胞介导的免疫调节. 而用siRNA封闭Treg细胞表面Gal-9可使Treg细胞对CD4+CD25- T细胞的抑制能力显著下调, 推测Gal-9低表达可能是Treg功能受损的一个机制. 据此推断, AIH中CD4+CD25- T效应细胞表面Tim-3与Treg细胞表面Gal-9可能是通过降低免疫易感性和损伤Treg细胞功能, 参与免疫调节受损.
2.1.3 Tim-3与原发性胆汁性肝硬变及硬化性胆管炎: 原发性胆汁性肝硬变(primary biliary cirrhosis, PBC)是一类以T细胞介导为主的慢性肝脏损害性疾病[40]. Lv等[41]建立小鼠肝损伤模型发现大量肝细胞凋亡, 大块肝组织出血坏死, CD4+ T细胞数目多, 且Tim-3表达上调. 用抗Tim-3单克隆抗体封闭Tim-3信号通路可加重肝脏损伤的病理学程度, 伴Tim-3+CD4+ T细胞数目显著增多, 提示Tim-3信号通路参与慢性肝损伤. 而用Gal-9预处理可显著改善肝脏病理学特征, 伴CD4+ T细胞数目及炎症因子分泌减少, 推测Tim-3与Gal-9结合可诱导CD4+ T细胞凋亡, 从而减少肝脏炎症因子浸润, 改善肝脏受损程度.
2.1.4 Tim-3与肝移植: 肝移植是治疗终末期肝病的一种有效治疗手段, 缺血再灌注损伤(ischemia/reperfusion injury, IRI)可致约10%的早期肝移植失败, 而Toll样受体4(toll-like receptor4, TLR4)信号是诱发肝IRI的关键因素[42]. Uchida等[43]研究显示Tim-3/Gal-9信号通路可通过减少IFN-γ的分泌来抑制TLR4表达, 负性调控肝IRI. Tim-3/TLR4信号互为调节决定肝IRI的严重程度, 故调节Tim-3/Gal-9信号通路有望提高肝移植成功率.
H. pylori是与慢性胃炎、胃溃疡、胃癌发病密切相关的病原微生物. Hu等[44]建立H. pylori感染Balb/c小鼠模型后发现, H. pylori感染组Tim-3 mRNA水平显著上调, 其表达与胃黏膜内Th1细胞因子IFN-γ和IL-12水平呈显著正相关, 而根除后小鼠脾脏Tim-3 mRNA的表达显著下降; 体外实验通过H. pylori活菌与Balb/c小鼠原代淋巴细胞共培养发现, 实验组Tim-3+ T细胞所占比例远高于对照组, 提示H. pylori感染可诱导Th1优势免疫反应, 而Tim-3的表达可反映Th1免疫反应, 因此可以通过调控Tim-3信号来防治H. pylori相关性疾病. Xie等[45-47]进一步用Tim-3单抗阻断Tim-3信号通路发现, Tim-3阻断对H. pylori疫苗接种小鼠和H. pylori感染小鼠免疫反应调控最终导致的结局不同, 前者在加剧炎症反应的同时, 有利于H. pylori的清除, 后者加剧炎症反应, 却不能清除H. pylori感染, 同时还发现Tim-3阻断可上调TLR4、髓样分化因子88(myeloid differentiation factor 88, MyD88)的表达和核因子-κB p65(nuclear factor-κB, NF-κB p65)活化, 降低CD4+CD25+Foxp3+Treg的数量, 增强了Th1免疫反应, 抑制了Th2免疫反应, 这可能是他增强H. pylori疫苗的免疫保护作用的机制, 但并不影响H. pylori自然感染小鼠胃黏膜内H. pylori定植密度, 以上研究证实Tim-3信号通路可通过调控TLR信号通路、Treg和Th免疫反应来影响H. pylori疫苗的免疫保护和H. pylori感染的免疫致病作用.
2.3.1 Tim-3与炎症性肠病: 炎症性肠病(inflammatory bowel disease, IBD), 主要包括溃疡性结肠炎(ulcerative colitis, UC)和克罗恩病(Crohn's disease, CD), 目前其病因和确切的发病机制并不明确, 一般认为是环境、遗传、免疫等因素共同作用于遗传易感个体, 产生过度免疫反应, 最终导致持续性肠道炎症. Morimoto等[48]研究发现, CD患者Th细胞表面Tim-3表达失调, 推测改变Th细胞表面Tim-3的表达可减轻IBD所致的炎性浸润. Li等[49]用重组Tim-3胞外蛋白封闭Tim-3预处理小鼠实验性结肠炎模型, 发现结肠炎症程度加重, Tim-3+CD4+ T细胞数量增多, Treg细胞数量减少, 促炎因子IFN-γ、IL-17、IL-23水平增高, IL-4水平下降, 提示Tim-3信号封闭加重结肠炎症可能与Treg细胞相关, 且Tim-3封闭启动Th1/Th17优势免疫应答. 同时, 淋巴细胞表面CD80/CD86和胞内CTLA-4表达下调, 推测Tim-3信号封闭介导的Th1优势免疫应答通过下调CD80和CTLA-4的表达, 活化Th1细胞功能, 进而抑制Treg细胞功能, 这些结果表明Tim-3可影响效应T细胞分化, 负性调控IBD的发展. 虽然大量研究表明Tim-3信号通路封闭可减少Gal-9/Tim-3介导的Th1细胞凋亡, 但是此研究并未发现这一现象, 具体原因尚不清楚. 钟玫君[50]用Tim-3单抗预处理小鼠实验性结肠炎模型, 证实了Li等的研究结果, 但与上述研究结果不同的是, 小鼠结肠炎症程度减轻. 进一步检测发现肠黏膜中MyD88、NF-κB p65蛋白表达下降, 而TLRs信号通路的负性调控因子单免疫球蛋白IL-1受体相关分子(single immunoglobulin IL-1R-related molecule, SIGIRR)蛋白表达上升. 结合前人研究, Tim-3信号通路在固有应答中可激活免疫应答, 推测该研究中Tim-3抗体通过增强对固有免疫应答TLRs/NF-κB信号通路的负性调控, 抑制TLRs/NF-κB信号通路激活, 从而减轻肠道炎症程度.
2.3.2 Tim-3与食物过敏所致肠道炎症浸润: 食物过敏在全世界范围内有高达2%-8%的发生率[51]. Chen等[52]研究显示, 食物过敏患者腹泻次数增多, 以肠道肥大细胞、嗜酸性粒细胞大量浸润, 抗原特异性CD4+ T细胞大量增殖, CD4+IL-4+ T细胞数目显著增多为特征, 且肠上皮细胞Galectin-9表达上调. 体外研究发现, 用RNA干扰技术敲除髓系未成熟树突状细胞的Tim-3基因, 可消除Gal-9诱导的促髓系树突状细胞成熟的效应, 显著减少Tim-4的分泌, 推测Gal-9通过与Tim-3相互作用活化肠道树突状细胞, 诱导Tim-4分泌, 介导Th2优势免疫应答, 最终导致肠道长期处于高敏状态.
近年来随着对Tim-3基因研究的深入, 已经发现Tim-3与众多疾病相关, 如自身免疫性疾病、过敏性疾病、炎症性疾病、病毒感染相关疾病、肿瘤等, 用Tim-3抗体或融合蛋白封闭Tim-3, 在一定程度上可改善或加重疾病程度, 提示Tim-3有望用于相关疾病的治疗, 但是其具体的分子机制目前尚不清楚. 是何种因素导致Tim-3在不同疾病中的表达水平及功能不同? 如多发性硬化患者脑脊液及外周血中T淋巴细胞低表达Tim-3, 病毒感染特异性CD8+ T细胞高表达Tim-3. Tim-3/Gal-9信通路在调控疾病的过程中是否与其他负性调控因子如PD-1、CTLA-4相关, 两者又是如何发挥效应的; 表达于固有免疫细胞表面的Tim-3是如何协调固有及适应性免疫应答反应的, 这些问题都有待今后进一步研究.
早期研究认为Tim-3特异性表达于Th1细胞表面, 他可作为区分Th1和Th2细胞的表面标志物, 并参与Th免疫调控. 近年来研究显示Tim-3在多种类型细胞表面均有表达, Tim-3与配体结合可调控免疫反应的多个环节, 并诱导细胞凋亡及清除凋亡细胞.
卢晓梅, 教授, 研究员, 新疆医科大学第一附属医院临床医学研究院; 秦建民, 主任医师, 上海中医药大学附属普陀医院普外科
Tim-3信号通路异常参与消化系疾病的发生发展, 激活或阻断此通路可改善或治愈相关疾病, 何种因素或机制导致Tim-3信号通路异常, 目前尚不清楚, 这是当前乃至今后的研究热点.
大量研究证实, Tim-3负性调控Th1/Th17细胞免疫应答, Tim-3表达失调参与自身免疫性疾病、过敏性疾病、病毒及细菌感染相关疾病等多种疾病.
本文较系统体现了Tim-3在消化系统疾病发生发展中的表现及功能, 指出Tim-3与TLR4信号通路相关.
Tim-3与配体及其相关调控因子在消化系疾病中表达失调或功能异常, 有望通过改变其表达或修复其功能, 指导临床疗效评估及药物的靶向治疗.
本文就Tim-3在肝病毒性肝炎、胃炎、炎症性肠病、消化系肿瘤等疾病发生、发展中生物学作用进行阐述, 具有一定的新颖性和临床参考价值.
| 1. | McIntire JJ, Umetsu SE, Akbari O, Potter M, Kuchroo VK, Barsh GS, Freeman GJ, Umetsu DT, DeKruyff RH. Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family. Nat Immunol. 2001;2:1109-1116. [PubMed] [DOI] |
| 2. | Chae SC, Song JH, Pounsambath P, Yuan HY, Lee JH, Kim JJ, Lee YC, Chung HT. Molecular variations in Th1-specific cell surface gene Tim-3. Exp Mol Med. 2004;36:274-278. [PubMed] [DOI] |
| 3. | Khademi M, Illés Z, Gielen AW, Marta M, Takazawa N, Baecher-Allan C, Brundin L, Hannerz J, Martin C, Harris RA. T Cell Ig- and mucin-domain-containing molecule-3 (TIM-3) and TIM-1 molecules are differentially expressed on human Th1 and Th2 cells and in cerebrospinal fluid-derived mononuclear cells in multiple sclerosis. J Immunol. 2004;172:7169-7176. [PubMed] |
| 4. | Nakae S, Iwakura Y, Suto H, Galli SJ. Phenotypic differences between Th1 and Th17 cells and negative regulation of Th1 cell differentiation by IL-17. J Leukoc Biol. 2007;81:1258-1268. [PubMed] [DOI] |
| 5. | Jones RB, Ndhlovu LC, Barbour JD, Sheth PM, Jha AR, Long BR, Wong JC, Satkunarajah M, Schweneker M, Chapman JM. Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J Exp Med. 2008;205:2763-2779. [PubMed] [DOI] |
| 6. | Anderson AC, Anderson DE, Bregoli L, Hastings WD, Kassam N, Lei C, Chandwaskar R, Karman J, Su EW, Hirashima M. Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science. 2007;318:1141-1143. [PubMed] [DOI] |
| 7. | Hou N, Zhao D, Liu Y, Gao L, Liang X, Liu X, Gai X, Zhang X, Zhu F, Ni M. Increased expression of T cell immunoglobulin- and mucin domain-containing molecule-3 on natural killer cells in atherogenesis. Atherosclerosis. 2012;222:67-73. [PubMed] [DOI] |
| 8. | Zhang Y, Ma CJ, Wang JM, Ji XJ, Wu XY, Moorman JP, Yao ZQ. Tim-3 regulates pro- and anti-inflammatory cytokine expression in human CD14+ monocytes. J Leukoc Biol. 2012;91:189-196. [PubMed] [DOI] |
| 9. | Cao E, Zang X, Ramagopal UA, Mukhopadhaya A, Fedorov A, Fedorov E, Zencheck WD, Lary JW, Cole JL, Deng H. T cell immunoglobulin mucin-3 crystal structure reveals a galectin-9-independent ligand-binding surface. Immunity. 2007;26:311-321. [PubMed] [DOI] |
| 10. | Lee J, Oh JM, Hwang JW, Ahn JK, Bae EK, Won J, Koh EM, Cha HS. Expression of human TIM-3 and its correlation with disease activity in rheumatoid arthritis. Scand J Rheumatol. 2011;40:334-340. [PubMed] [DOI] |
| 11. | Kearley J, McMillan SJ, Lloyd CM. Th2-driven, allergen-induced airway inflammation is reduced after treatment with anti-Tim-3 antibody in vivo. J Exp Med. 2007;204:1289-1294. [PubMed] [DOI] |
| 12. | Sharma S, Sundararajan A, Suryawanshi A, Kumar N, Veiga-Parga T, Kuchroo VK, Thomas PG, Sangster MY, Rouse BT. T cell immunoglobulin and mucin protein-3 (Tim-3)/Galectin-9 interaction regulates influenza A virus-specific humoral and CD8 T-cell responses. Proc Natl Acad Sci U S A. 2011;108:19001-19006. [PubMed] [DOI] |
| 13. | Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, Manning S, Greenfield EA, Coyle AJ, Sobel RA. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature. 2002;415:536-541. [PubMed] [DOI] |
| 14. | Jayaraman P, Sada-Ovalle I, Beladi S, Anderson AC, Dardalhon V, Hotta C, Kuchroo VK, Behar SM. Tim3 binding to galectin-9 stimulates antimicrobial immunity. J Exp Med. 2010;207:2343-2354. [PubMed] [DOI] |
| 15. | Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6:1245-1252. [PubMed] [DOI] |
| 16. | Türeci O, Schmitt H, Fadle N, Pfreundschuh M, Sahin U. Molecular definition of a novel human galectin which is immunogenic in patients with Hodgkin's disease. J Biol Chem. 1997;272:6416-6422. [PubMed] [DOI] |
| 17. | Wada J, Kanwar YS. Identification and characterization of galectin-9, a novel beta-galactoside-binding mammalian lectin. J Biol Chem. 1997;272:6078-6086. [PubMed] [DOI] |
| 18. | Anderson AC, Anderson DE. TIM-3 in autoimmunity. Curr Opin Immunol. 2006;18:665-669. [PubMed] [DOI] |
| 19. | Kashio Y, Nakamura K, Abedin MJ, Seki M, Nishi N, Yoshida N, Nakamura T, Hirashima M. Galectin-9 induces apoptosis through the calcium-calpain-caspase-1 pathway. J Immunol. 2003;170:3631-3636. [PubMed] |
| 20. | Seki M, Oomizu S, Sakata KM, Sakata A, Arikawa T, Watanabe K, Ito K, Takeshita K, Niki T, Saita N. Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis. Clin Immunol. 2008;127:78-88. [PubMed] [DOI] |
| 21. | Bi S, Earl LA, Jacobs L, Baum LG. Structural features of galectin-9 and galectin-1 that determine distinct T cell death pathways. J Biol Chem. 2008;283:12248-12258. [PubMed] [DOI] |
| 22. | DeKruyff RH, Bu X, Ballesteros A, Santiago C, Chim YL, Lee HH, Karisola P, Pichavant M, Kaplan GG, Umetsu DT. T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells. J Immunol. 2010;184:1918-1930. [PubMed] [DOI] |
| 23. | Nakayama M, Akiba H, Takeda K, Kojima Y, Hashiguchi M, Azuma M, Yagita H, Okumura K. Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. Blood. 2009;113:3821-3830. [PubMed] [DOI] |
| 24. | Webster GJ, Reignat S, Brown D, Ogg GS, Jones L, Seneviratne SL, Williams R, Dusheiko G, Bertoletti A. Longitudinal analysis of CD8+ T cells specific for structural and nonstructural hepatitis B virus proteins in patients with chronic hepatitis B: implications for immunotherapy. J Virol. 2004;78:5707-5719. [PubMed] [DOI] |
| 25. | Chisari FV, Isogawa M, Wieland SF. Pathogenesis of hepatitis B virus infection. Pathol Biol (Paris). 2010;58:258-266. [PubMed] [DOI] |
| 26. | Wu W, Shi Y, Li J, Chen F, Chen Z, Zheng M. Tim-3 expression on peripheral T cell subsets correlates with disease progression in hepatitis B infection. Virol J. 2011;8:113. [PubMed] [DOI] |
| 27. | Ju Y, Hou N, Meng J, Wang X, Zhang X, Zhao D, Liu Y, Zhu F, Zhang L, Sun W. T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) mediates natural killer cell suppression in chronic hepatitis B. J Hepatol. 2010;52:322-329. [PubMed] [DOI] |
| 28. | Wu W, Shi Y, Li S, Zhang Y, Liu Y, Wu Y, Chen Z. Blockade of Tim-3 signaling restores the virus-specific CD8+ T-cell response in patients with chronic hepatitis B. Eur J Immunol. 2012;42:1180-1191. [PubMed] [DOI] |
| 29. | Golden-Mason L, Palmer BE, Kassam N, Townshend-Bulson L, Livingston S, McMahon BJ, Castelblanco N, Kuchroo V, Gretch DR, Rosen HR. Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells. J Virol. 2009;83:9122-9130. [PubMed] [DOI] |
| 30. | McMahan RH, Golden-Mason L, Nishimura MI, McMahon BJ, Kemper M, Allen TM, Gretch DR, Rosen HR. Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity. J Clin Invest. 2010;120:4546-4557. [PubMed] [DOI] |
| 31. | Vali B, Jones RB, Sakhdari A, Sheth PM, Clayton K, Yue FY, Gyenes G, Wong D, Klein MB, Saeed S. HCV-specific T cells in HCV/HIV co-infection show elevated frequencies of dual Tim-3/PD-1 expression that correlate with liver disease progression. Eur J Immunol. 2010;40:2493-2505. [PubMed] [DOI] |
| 32. | Zhang Y, Ma CJ, Wang JM, Ji XJ, Wu XY, Jia ZS, Moorman JP, Yao ZQ. Tim-3 negatively regulates IL-12 expression by monocytes in HCV infection. PLoS One. 2011;6:e19664. [PubMed] [DOI] |
| 33. | Mengshol JA, Golden-Mason L, Arikawa T, Smith M, Niki T, McWilliams R, Randall JA, McMahan R, Zimmerman MA, Rangachari M. A crucial role for Kupffer cell-derived galectin-9 in regulation of T cell immunity in hepatitis C infection. PLoS One. 2010;5:e9504. [PubMed] [DOI] |
| 34. | Hu S, Xie Y, Zhou N, Jin L, Tan Y, Liu D, Gong Y, Liu L, Liu J, Liu W. Expression of T-cell immunoglobulin- and mucin-domain-containing molecules-1 and -3 (Tim-1 and Tim-3) in Helicobacter pylori infection. Helicobacter. 2011;16:373-381. [PubMed] [DOI] |
| 35. | Li H, Wu K, Tao K, Chen L, Zheng Q, Lu X, Liu J, Shi L, Liu C, Wang G. Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology. 2012;56:1342-1351. [PubMed] [DOI] |
| 36. | Li Z, Liu Z, Zhang G, Han Q, Li N, Zhu Q, Lv Y, Chen J, Xing F, Wang Y. TIM3 gene polymorphisms in patients with chronic hepatitis B virus infection: impact on disease susceptibility and hepatocellular carcinoma traits. Tissue Antigens. 2012;80:151-157. [PubMed] [DOI] |
| 37. | Li Z, Li N, Zhu Q, Zhang G, Han Q, Zhang P, Xun M, Wang Y, Zeng X, Yang C. Genetic variations of PD1 and TIM3 are differentially and interactively associated with the development of cirrhosis and HCC in patients with chronic HBV infection. Infect Genet Evol. 2013;14:240-246. [PubMed] [DOI] |
| 38. | Longhi MS, Hussain MJ, Mitry RR, Arora SK, Mieli-Vergani G, Vergani D, Ma Y. Functional study of CD4+CD25+ regulatory T cells in health and autoimmune hepatitis. J Immunol. 2006;176:4484-4491. [PubMed] |
| 39. | Liberal R, Grant CR, Holder BS, Ma Y, Mieli-Vergani G, Vergani D, Longhi MS. The impaired immune regulation of autoimmune hepatitis is linked to a defective galectin-9/tim-3 pathway. Hepatology. 2012;56:677-686. [PubMed] [DOI] |
| 40. | Hirschfield GM, Gershwin ME. The immunobiology and pathophysiology of primary biliary cirrhosis. Annu Rev Pathol. 2013;8:303-330. [PubMed] [DOI] |
| 41. | Lv K, Zhang Y, Zhang M, Zhong M, Suo Q. Galectin-9 ameliorates Con A-induced hepatitis by inducing CD4(+)CD25(low/int) effector T-Cell apoptosis and increasing regulatory T cell number. PLoS One. 2012;7:e48379. [PubMed] [DOI] |
| 42. | Zhai Y, Shen XD, O'Connell R, Gao F, Lassman C, Busuttil RW, Cheng G, Kupiec-Weglinski JW. Cutting edge: TLR4 activation mediates liver ischemia/reperfusion inflammatory response via IFN regulatory factor 3-dependent MyD88-independent pathway. J Immunol. 2004;173:7115-7119. [PubMed] |
| 43. | Uchida Y, Ke B, Freitas MC, Yagita H, Akiba H, Busuttil RW, Najafian N, Kupiec-Weglinski JW. T-cell immunoglobulin mucin-3 determines severity of liver ischemia/reperfusion injury in mice in a TLR4-dependent manner. Gastroenterology. 2010;139:2195-2206. [PubMed] [DOI] |
| 44. | Hu S, Xie Y, Zhou N, Jin L, Tan Y, Liu D, Gong Y, Liu L, Liu J, Liu W. Expression of T-cell immunoglobulin- and mucin-domain-containing molecules-1 and -3 (Tim-1 and Tim-3) in Helicobacter pylori infection. Helicobacter. 2011;16:373-381. [PubMed] [DOI] |
| 45. | Xie Y. The influence of blocking Tim-3 signal pathway on immune pathopoiesis of H. pylori infection and TLRs signal pathway. J Gastroenterol Hepatol. 2011;26:268-268. |
| 46. | Xie Y. The influence of blocking Tim-3 signal pathway on immune pathopoiesis of H. pylori infection and Th immune respond. J Gastroenterol Hepatol. 2011;26:17. |
| 47. | Xie Y. The influence of blocking Tim-3 signal pathway on immune protection of H. pylori vaccine and Th immune respond. J Gastroenterol Hepatol. 2011;26:93. |
| 48. | Morimoto K, Hosomi S, Yamagami H, Watanabe K, Kamata N, Sogawa M, Machida H, Okazaki H, Tanigawa T, Nagahara H. Dysregulated upregulation of T-cell immunoglobulin and mucin domain-3 on mucosal T helper 1 cells in patients with Crohn's disease. Scand J Gastroenterol. 2011;46:701-709. [PubMed] [DOI] |
| 49. | Li X, Chen G, Li Y, Wang R, Wang L, Lin Z, Gao X, Feng J, Ma Y, Shen B. Involvement of T cell Ig Mucin-3 (Tim-3) in the negative regulation of inflammatory bowel disease. Clin Immunol. 2010;134:169-177. [PubMed] [DOI] |
| 51. | Obeng BB, Amoah AS, Larbi IA, Yazdanbakhsh M, van Ree R, Boakye DA, Hartgers FC. Food allergy in Ghanaian schoolchildren: data on sensitization and reported food allergy. Int Arch Allergy Immunol. 2011;155:63-73. [PubMed] [DOI] |