修回日期: 2017-05-15
接受日期: 2017-05-22
在线出版日期: 2017-08-18
T淋巴细胞免疫球蛋白黏蛋白分子(T-cell immunoglobulin domain and mucin domain-containing molecule, Tim)-3是Tim家族中的一员, 为近年来新发现的一种在辅助Ⅰ型T淋巴细胞(Help T cell 1, Th1)上特异性表达的Ⅰ型细胞表面分子. Tim-3作为负性调节因子通过与其配体Galectin-9结合引起细胞死亡, 进而调控Th1型细胞功能. Tim-3还表达于其他类型细胞表面, 如自然杀伤细胞、树突状细胞和单核细胞, 对自身免疫性疾病和其他免疫介导的疾病进行免疫调控. 对Tim-3在不同细胞不同免疫条件下的功能以及如何调节进行研究, 将有利于研发Tim-3的潜在治疗作用. 近年来大量研究显示Tim-3通道与肝脏疾病发生发展有着密切关系, 本文就其在肝脏疾病中的调节作用做一总结.
核心提要: T淋巴细胞免疫球蛋白黏蛋白分子(T-cell immunoglobulin domain and mucin domain-containing molecule, Tim)-3在维持宿主免疫耐受中具有十分重要的作用, 通过对天然免疫和适应性免疫进行调节广泛参与多种肝脏疾病的发生发展. 通过对Tim-3功能及其调节方式的研究, 将有助于研发其潜在的治疗效用, 尤其在自身免疫性肝病临床治疗中.
引文著录: 唐映梅, 徐加敏. Tim-3在肝脏疾病中的调节作用. 世界华人消化杂志 2017; 25(23): 2080-2087
Revised: May 15, 2017
Accepted: May 22, 2017
Published online: August 18, 2017
T-cell immunoglobulin domain and mucin domain-containing molecule (Tim)-3 is a member of the Tim family. As a newly found type-1 surface molecule in recent years, Tim-3 is specifically expressed on T helper 1(Th1) cells and acts as a negative regulator of Th1 cell function by triggering cell death upon interaction with its ligand, galectin-9. Tim-3 is also expressed on other cell types, such as natural killer cells, dendritic cells and monocytes. Furthermore, Tim-3 participates in the regulation of autoimmune diseases and other immune-mediated diseases. An understanding of the function of Tim-3 in different cell types under different immune conditions and the underlying regulatory mechanism will be helpful to reveal the therapeutic potential of Tim-3. Numerous studies have demonstrated a strong association between Tim-3 pathway and the development of liver diseases in recent years. Here we review the regulatory role of Tim-3 in liver diseases.
- Citation: Tang YM, Xu JM. Regulatory role of Tim-3 in liver diseases. Shijie Huaren Xiaohua Zazhi 2017; 25(23): 2080-2087
- URL: https://www.wjgnet.com/1009-3079/full/v25/i23/2080.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v25.i23.2080
T淋巴细胞免疫球蛋白黏蛋白分子(T-cell immunoglobulin domain and mucin domain-containing molecule, Tim)-3为一种表达于辅助Ⅰ型T淋巴细胞(Help T cell 1, Th1)上的特异性表面分子, 是Tim家族的成员之一, 在免疫介导的疾病中具有十分重要的作用. Tim-3可通过与天然配体半乳糖凝激素-9(Galectin-9)结合, 给T淋巴细胞提供一种负性共刺激信号, 触发Th1细胞死亡进而下调Th1型细胞活性[1,2]. 研究[3]显示, Tim-3/Galectin-9通道可抑制幼稚T细胞向能分泌白介素-17(interleukin-17, IL-17)的Th17细胞分化. Tim-3信号通道在体内有抑制Th1和Th17细胞相关的适应性炎症反应和维持机体免疫耐受能力. 此外, Tim-3也表达于活化后的Th17细胞、CD8+和细胞毒性T淋巴细胞表面, Tim-3在CD4+和CD8+上表达失调与自身免疫性疾病、病毒感染和肿瘤疾病密切相关[4-6].
Tim-3除了与适应性免疫有关外, 还调节天然免疫[7,8]. 大量研究表明, Tim-3也表达于树突状细胞、自然杀伤(natural killer, NK)细胞和单核细胞上, 而Tim-3在这些细胞上过表达与病情恶化有关. Tim-3分子的多态性与疾病易感性也有一定关系, 研究[9-11]发现慢性乙型病毒性肝炎和丙型病毒性肝炎发生发展与Tim-3多态性有关. Tim-3/Galectin-9通道参与多种疾病发生发展, 包括过敏、自身免疫性疾病、移植免疫、肿瘤、感染等多种疾病, Tim-3分子在未来临床治疗中将成为新的靶点[12-14]. 近年来Tim-3在肝脏疾病方面研究成为新的热点, Tim-3对肝脏疾病的影响日益受到人们的重视, 以下就Tim-3分子在肝脏疾病中的调节作用给予综述.
近年来, 大量研究凸显出Tim-3在肝炎病毒感染过程中对宿主免疫调节的重要性. Tim-3作为负性调节因子, 能够下调天然免疫和适应性免疫, 这对肝炎病毒逃避宿主免疫攻击十分有利. 乙型肝炎病毒(hepatitis B virus, HBV)和丙型肝炎病毒(hepatitis C virus, HCV)感染者易演变成为慢性感染, 可进展为肝硬化、肝衰竭和肝细胞癌(hepatocellular carcinoma, HCC). 而Tim-3的多态性对肝炎病毒感染慢性化以及进一步恶化为肝硬化和HCC有一定作用, 但目前研究依然停留在对Tim-3表达与病毒感染之间的关系的研究, 对具体调控机制尚未完全知晓.
Tim-3在甲型肝炎病毒(hepatitis A virus, HAV)感染中的相关研究相对较少, 但有提示二者存在一定关系. HAV经粪-口在人群中传播, 首先识别宿主细胞相应的受体并黏附于细胞表面, 进而侵入细胞体内. 上个世纪末, 曾在非洲绿猴细胞上鉴定出HAV细胞受体-1(HAV cellular receptor-1, HAVcr-1), 随后发现人类也存在相应HAV受体HuHAVcr-1[15,16]. HuHAVcr-1即Tim-1, 也是Tim家族中的一员, 在肾脏和肝脏中最先被发现, 选择性表达于分化的Th2细胞表面, 参与Th2型免疫应答反应. Tim-3又名HAVcr-2, 其胞外段免疫球蛋白区与Tim-1具有57%的同源性[17], 因此Sui等[18]推断Tim-3为HAV的另一细胞受体, 他们的后续研究结果表明Tim-3分子并未与HAV直接结合, 但是能够促进HAV侵入靶细胞内. Tim-3/HAVcr-2能够调节巨噬细胞活性和功能[1], 且在Th1型免疫调节中作为负性细胞因子, Tim-3可能通过其信号通道转换为一种对Th1细胞、巨噬细胞及DC细胞等适应性或天然免疫细胞的负性调节信号, 进而有利于HAV对机体的侵入. 目前, Tim-3在HAV感染方面研究甚少, Tim-3对HAV感染的促进关系尚缺乏足够证据, 其具体机制仍需大量研究进一步明确.
Tim-3在乙型病毒性肝炎中具有十分重要作用, 尤其对慢性乙型病毒性肝炎(chronic hepatitis B, CHB)的演变及进程的调节更为突出. 研究[4]发现, 同健康人群比较, 急性乙型病毒性肝炎(acute hepatitis B, AHB)和CHB患者外周血CD4+和CD8+T淋巴细胞Tim-3表达明显增多. 在CHB患者中, 重度组Tim-3+T淋巴细胞比例多于中度组, 且与丙氨酸氨基转移酶(alanine aminotransferase, ALT)、天冬氨酸转氨酶、总胆红素及国际标准化比值呈正相关, 经抗病毒治疗后, 处于缓解期的CHB和康复期的AHB患者外周血CD4+和CD8+T淋巴细胞Tim-3表达均有下降, 提示Tim-3基因高表达在CHB患者肝脏免疫损伤调节中占有十分重要的作用.
Tim-3还可能参与HBV感染慢性化过程. 近年来, 大量研究发现CHB患者特异性T淋巴细胞耗竭和免疫应答能力减弱甚至缺失, 由于CD4+和CD8+T淋巴细胞应答不足, HBV清除受限, 进而促进HBV感染慢性化, 而该现象与Tim-3有着千丝万缕的关系. Dinney等[19]研究发现, 在无症状HBV感染、活动期CHB和HBV相关性HCC三组患者中, 特异性CD8+T细胞数相似, 但第一组较后两组能分泌大量干扰素(interferon, IFN)-γ和肿瘤坏死因子-α(tumor necrosis factor α, TNF-α), 且Tim-3阴性细胞频数较高. Nebbia等[20]发现CHB患者Tim-3和Galectin-9表达增高. Tim-3高表达于HBV特异性T淋巴细胞, 尤其是CD8+效应T淋巴细胞. 这些表达Tim-3的特异性T淋巴细胞易触发Galectin-9而引发自身凋亡, 分泌IFN-γ和TNF-α的能力下降. 封闭Tim-3/Galectin-9通道后, 特异性CD8+T淋巴细胞功能明显恢复, IFN-γ和TNF-α大量分泌, 对HBV的免疫应答效率增高[20]. 通过以上结果提示Tim-3在CHB患者T淋巴细胞耗竭中起到关键的调节作用. 除T淋巴细胞耗竭现象外, Gao等[21]还在他们研究中发现, 包括免疫耐受期和免疫活动期在内的CHB患者外周血CD14+单核细胞(mononuclear cells, Mo)表面Tim-3分子及其mRNA表达均显著高于健康对照组, 其中免疫活动期期CHB患者外周血CD14+Mo细胞表面Tim-3分子表达还与ALT呈正相关. 可见Mo细胞表面Tim-3分子表达与CHB发作密切相关, 但无论在T淋巴细胞耗竭还是Mo细胞免疫应答调节中, Tim-3/Galectin-9信号通路通过何种机制进行调节, 目前仍不能够明确, 还需进一步深入研究.
Tim-3的多态性在HBV感染中有一定影响作用. 研究[9]发现, Tim-3多态性基因片段-1516G/T能够影响CHB易感性和HBV感染相关性HCC, 研究结果也潜在揭示Tim-3在慢性HBV感染及HBV感染相关性HCC中可诱导HBV特异性CD8+T淋巴细胞失能和耗竭. 另一项研究[10]显示, Tim-3基因变异在HBV感染进程中具有十分重要作用, 一些特定的多肽性基因还可能增加患HBV相关性HCC的几率, 促进乙肝表面抗原的清除. 对Tim-3多态性和表观遗传学的研究, 有助于预防HBV感染以及对感染后期各阶段实施针对性干扰, 实现个性化治疗的目的.
大量研究结果表明, 慢性丙型病毒性肝炎(chronic hepatitis C, CHC)患者同样存在Tim-3介导的T淋巴细胞失能和耗竭现象, 导致HCV持续感染. Tim-3在HCV感染过程中作为负性调节因子高表达于CD4+、CD8+等淋巴细胞表面, 封闭Tim-3/Galectin-9通道能够逆转效应细胞的凋亡, 恢复宿主抗病毒能力. Tim-3还能调控调节性T细胞(regulatery T cell, Treg细胞)与效应T细胞之间的平衡, 一方面促进Foxp3+ Treg细胞增殖, 上调Treg细胞功能, 一方面诱导抗HCV效应T细胞凋亡, 降低宿主抗病毒免疫应答能力, 导致机体免疫耐受[22,23]. 在对HCV的天然免疫应答中, Tim-3的负性调节作用尤为关键, Tim-3可协同程序性死亡因子1和抑制性细胞因子1, 限制信号转导子和转录激动子1的磷酸化水平, 进而调控单核/巨噬细胞, 抑制IL-12的分泌[24]. Tim-3通过对Mo细胞的免疫调节影响IL-12/IL-23之间的平衡, 促进TH17淋巴细胞的分化, 大量分泌IL-17, 为HCV持续感染及自身免疫性疾病的形成创造良好的环境[25]. NK细胞是免疫系统不可缺少的天然免疫细胞, 能够通过直接或间接致死靶细胞, 清除入侵的病毒. HCV能够破坏机体正常的免疫系统, 以利于逃避宿主免疫攻击和持续感染. 研究[26,27]发现, CHC患者体内NK细胞明显减少, 其免疫功能也出现异常. 然而Tim-3高表达于NK细胞, 尤其是CD56dimNK细胞. 可见, Tim-3在HCV感染过程中对NK细胞免疫功能进行调节. Tim-3被认为是NK细胞成熟的标记物之一, 通过与其抗体相互作用后可抑制NK细胞杀伤活性, 提示与表达Tim-3配体的靶细胞作用后对NK细胞功能进行下调[28]. 值得注意的是, Tim-3高表达可能是HCV感染引起的NK细胞功能失调的结果, 而不是失调的原因. miR-155可通过调控Tim-3的表达进而影响NK细胞IFN-γ的分泌[26], 其调节机制可能为抗HCV治疗提供新靶点.
自身免疫性肝病(autoimmune liver disease, AILD)是一组由自身免疫介导的慢性肝胆系统损伤性疾病, 包括自身免疫性肝炎、原发性胆汁胆管炎和原发性硬化性胆管炎, 其病因及发病机制目前尚未完全知晓. 近年来Tim-3在自身免疫性疾病中的研究已成为焦点, 但是在AILD方面的研究较少.
CD4+效应T淋巴细胞在AIH中占有主导地位, 能通过大量增殖和分泌IFN-γ损伤肝细胞. Longhi等[29-31]研究表明, 在AILD中CD4+效应T淋巴细胞免疫应答能力取决于Treg细胞免疫调节功能. 而由于Treg细胞功能缺陷导致不能正常调控效应细胞的增殖和IFN-γ等效应细胞因子的释放. 此后研究[5]发现AIH患者Tim-3和Galectin-9均低表达于效应T淋巴细胞和Treg细胞表面, 并导致Treg细胞功能缺陷和效应T淋巴细胞对Treg细胞调控的敏感性降低. Galectin-9+Treg细胞除了能够诱导效应细胞凋亡外, 还能通过分泌IL-10抑制免疫反应[5]. Th17细胞也参与AILD的发生发展, Lv等[32]研究提示Tim-3可能通过Treg细胞对Th17细胞进行免疫调控.
效应T淋巴细胞和Treg细胞功能缺陷现象不仅出现在AIH中, 还出现在自身免疫性肝炎/原发性硬化性胆管炎重叠综合征中, Tim-3和Galectin-9表达也较健康受试者下调[5]. 此外, 研究[33]发现通过干扰Tim-3/Galectin-9信号通道能够改善刀豆素A诱导的免疫性肝损伤. Galectin-9能够有选择的诱导CD4+效应T淋巴细胞凋亡, 还能有效地减少IFN-γ, TNF-α和IL-6等促炎因子释放. Tim-3/Galectin-9信号通道能够提高效应T淋巴细胞凋亡敏感性和Treg细胞凋亡耐受性[23], 因此Tim-3可能通过调控CD4+效应T淋巴细胞和Treg细胞之间的平衡关系, 进而抑制失控的炎性反应, 改善免疫性肝损伤. 综上研究结果, 可推测在AILD中Tim-3和Galectin-9的表达减少, 进而丧失限制炎性免疫的能力, 但是此推测尚缺乏大量的研究证实.
近期有研究提示Tim-3参与非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD)的发生发展. Tim-3/Galectin-9信号通道一方面诱导激活的NKT细胞凋亡, 一方面又通过调控肝Kuffer细胞分泌IL-15促进NKT细胞的增殖, 进而影响NKT细胞数量及功能, 调节肝脏局部微环境[34]. NKT细胞在NAFLD形成机制中具有十分重要作用, 局部或其他微环境因素引起的NKT细胞的凋亡可导致慢性炎症产生, 进一步形成肝细胞脂肪变性和胰岛素抵抗[35,36]. 增加肝NKT细胞能够逆转肝细胞脂肪变性和胰岛素抵抗, 还能下调炎性信号通道. Tim-3主要表达于CD4+NKT细胞表面, 上调Tim-3表达后肝细胞脂肪变性持续进展, 经Galectin-9诱导后大量CD4+NKT细胞凋亡[34], 由此可见Tim-3参与肝细胞脂肪变性的发生发展. 除对饮食调节外, 对Tim-3的深入研究将可能为NAFLD的治疗提供新的靶点.
近年来有研究提示Tim-3对肝纤维化及肝硬化的形成具有促进作用. Th1/Th2之间免疫平衡影响IFN-γ和IL-4的分泌. NK细胞也能分泌IFN-γ并通过拮抗活化的星状细胞起到抗肝纤维化作用[37], IL-4则能够促进肝纤维化进展. Tim-3负性调控Th1型免疫, 出现Th2型免疫偏移[1], 进而对肝纤维化进展进行调控[38]. Wu等[39]研究表明, 晚期血吸虫病患者外周血CD56+NK细胞Tim-3表达呈上调, 并与患者肝纤维化指标三型前胶原N端肽、层黏连蛋白、Ⅳ型胶原和IL-4水平呈正相关, 与IFN-γ水平呈负相关. Tim-3基因多态性对肝脏疾病病程、肝硬化和HCC的形成也有一定关系[9,40], 而Tim-3/Galectin-9信号通道可通过调节Th1/Th2进而调控肝脏疾病进程[20]. 目前Tim-3对肝硬化的调节及通过何种方式影响其形成尚缺乏研究证实.
近期有研究[41,42]突出肿瘤微环境在HCC发生发展、侵袭和转移过程中的重要调节作用, 而包括肿瘤侵袭的淋巴细胞和肿瘤相关巨噬细胞在内的免疫细胞构成了肿瘤微环境的重要间质成分. Yan等[6]研究发现Tim-3/Galectine-9信号通道参与HCC的发生发展. Tim-3和Galectine-9在HCC组织中表达明显增多, Galectine-9通过与Tim-3结合促进Treg细胞增殖, 并诱导CD8+T淋巴细胞凋亡, 同时减少IFN-γ的分泌. 此外, Tim-3在外周血单核细胞和HCC组织中的巨噬细胞上的表达显著增高, 且Tim-3的表达与HCC分期呈正相关, 与患者存活数呈负相关[43]. HCC患者体内转化生长因子-β也明显增多, 并能选择性的激活巨噬细胞和促进Tim-3在其表面大量表达. Tim-3可通过上调IL-6的分泌促进HCC的生长, 对Tim-3进行干扰后, 显著抑制HCC的生长和扩散. 根据以上研究结果, Tim-3可下调患者对HCC的免疫应答能力, 以利于癌细胞的持续发展和扩散. Tim-3在HCC中的表达还与其基因多肽性有关, rs10053538基因型可显著提高Tim-3在癌组织、癌旁组织和肝硬化组织中的表达[44]. 然而有报道[45,46]Tim-3能够发挥抗肿瘤免疫应答的作用, 其原因可能是不同组织决定Tim-3的表型和在肿瘤微环境中的作用.
目前肝移植已成为各种原因所致的严重终末期肝病的最佳治疗措施, 但术后排斥反应一直是影响肝移植疗效的重要问题. Tim-3对Th1型免疫进行负性调控[1], 在维持机体正常免疫耐受过程中具有十分重要作用. 在同型异体免疫和移植排斥中, Tim-3具有维持机体内环境稳态的作用. Tim-3通道可通过Treg细胞抑制抗原特异性效应T淋巴细胞功能, 进而下调Th1型免疫介导的免疫损伤, 减少局部炎性反应, 促进免疫耐受的形成. 研究[47,48]显示在移植物抗宿主疾病中, Tim-3及其配体表达显著增多, 尤其Tim-3在包括供体和受体来源的肝CD8+T细胞表面表达急剧增加. 阻断Tim-3通道后, IFN-γ分泌和供体来源的特异性CD8+T细胞数量增加, 抗宿主免疫反应出现恶化[49]. Liu等[50,51]研究表明, Tim-3/Galectine-9信号通道可通过抑制肝移植受体T淋巴细胞活性和促进CD4+T淋巴细胞凋亡, 进而负性调控Th1型免疫反应, 减轻原位肝移植保存损伤和缺血再灌注损伤. Tim-3通过调节Th1型免疫对维持肝移植患者内环境稳态和减轻免疫损伤具有极其重要的作用, 为解决肝移植免疫损伤提供新的靶点, 提高肝移植的成活率.
Tim-3作为负性免疫调节因子, 对维持机体免疫耐受和内环境稳态具有十分重要作用. Tim-3不仅对适应性免疫进行调节, 还参与天然免疫, 尤其对NK细胞和单核巨噬系统的调控. 在目前Tim-3与肝脏疾病的研究中, 主要集中于对Tim-3表达水平与疾病的关系以及其信号通道对肝脏疾病的免疫调节作用, 但对Tim-3在肝脏疾病中的调节通过何种方式及其具体机制尚缺乏足够研究. 近年来在Tim-3基因多态性与肝脏疾病研究也越来越多, 作为新的治疗靶点, 对其调节机制进一步研究, 渴望能够为肝脏疾病临床治疗提供新的治疗方案.
T淋巴细胞免疫球蛋白黏蛋白分子(T-cell immunoglobulin domain and mucin domain-containing molecule, Tim)-3是Tim家族中的重要一员, 作为负性调控因子下调Ⅰ型T淋巴细胞型免疫. Tim-3对天然免疫和适应性免疫的调控, 进而参与多种免疫性疾病. Tim-3分子的多态性与疾病易感性也有一定关系, 因此将Tim-3作为一种新靶点, 为临床治疗提供新的策略.
Tim-3在病毒持续感染、肿瘤微环境和自身免疫性肝病中具有十分重要调节作用, 可减轻宿主-移植物之间的排斥反应. 但是, 目前仍然处于对Tim-3表达的研究阶段, 在不同的疾病中不同的细胞上以及具体的调节通道尚需要大量的深入研究来阐明.
本文系统阐述了Tim-3研究在肝脏疾病中免疫调节的重要性, 以及揭示亟待解决的问题, 为后续研究提供一定的指导.
辅助抗病毒和抗癌、抑制自身免疫性肝病炎症反应、减轻移植排斥反应的治疗具有潜在的应用前景.
程书权, 教授, 主任医师, 研究生导师, 桂林医学院第三附属医院(桂林市传染病医院, 桂林市第三人民医院)肝病科; 张福奎, 主任医师, 首都医科大学附属北京友谊医院肝病中心
本文对Tim-3分子在肝脏疾病中的调节作用进行了全面综述, 对疗程医务人员开阔视野、把握前沿具有一定参考价值.
手稿来源: 邀请约稿
学科分类: 胃肠病学和肝病学
手稿来源地: 云南省
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