• 点赞 0
  • 分享 0
• 综述 •
Th22细胞在人类常见病毒感染中的研究进展
中华临床感染病杂志, 2021,14(3) : 233-240. DOI: 10.3760/cma.j.issn.1674-2397.2021.03.015
摘要

初始CD4+T淋巴细胞在接受抗原刺激后可分化为不同的辅助性T细胞亚群，并分泌相应的细胞因子发挥生物学效应。Th22细胞是近年被发现的新型CD4+T淋巴细胞亚群，不同于Th1、Th2和Th17细胞等亚群，Th22细胞分泌白细胞介素(IL)-22、IL-13和肿瘤坏死因子(TNF)-α等因子，不分泌IL-17、IL-4、干扰素-γ(IFNγ)等因子，表达CCR4、CCR6和CCR10趋化因子受体，其中IL-22被认为是Th22细胞的主要效应分子。Th22细胞的功能和分化的机制不断被完善，且在人类常见病毒感染中发挥重要作用。本文就Th22细胞的特征与功能及其分化机制，以及IL-22在人类常见病毒感染中的作用作一介绍，为人类病毒的防治提供新的免疫策略。

引用本文: 崔大伟, 姚妮, 吕燕, 等.  Th22细胞在人类常见病毒感染中的研究进展 [J] . 中华临床感染病杂志, 2021, 14(3) : 233-240. DOI: 10.3760/cma.j.issn.1674-2397.2021.03.015.
参考文献导出:   Endnote    NoteExpress    RefWorks    NoteFirst    医学文献王
扫  描  看  全  文

正文
作者信息
基金 0  关键词  0
English Abstract
评论
阅读 0  评论  0
相关资源
引用 | 论文 | 视频

版权归中华医学会所有。

未经授权，不得转载、摘编本刊文章，不得使用本刊的版式设计。

除非特别声明，本刊刊出的所有文章不代表中华医学会和本刊编委会的观点。

辅助性CD4+T(Th)淋巴细胞，主要包括Th1、Th2、Th17、Th9、滤泡辅助性T细胞(Tfh)以及调节性T(Treg)细胞等[1,2,3]。近年来研究发现一种新型的Th22细胞，高分泌白细胞介素-22(IL-22)，但不分泌IL-17、IL-4和干扰素-γ(IFNγ)等细胞因子[4,5,6,7,8]。Th22细胞不同于Thl、Th2和Th17细胞等Th细胞，但与Th细胞又存在关联，如在一定条件下，Th17细胞也可高表达IL-22因子[5,9,10,11]。利用全转录组微阵列分析技术对Th17、Th22细胞进行mRNA转录谱分析，证实Th22与Th17细胞的差异，进而确定Th22细胞是独立的细胞谱系[12]。Th22细胞高表达趋化因子受体-4(CCR4)、CCR6和CCR10分子，参与皮肤的自稳调节和病理过程，促进血管生成，加快伤口愈合[6,11]。研究显示，IL-6和肿瘤坏死因子-α(TNF-α)能够诱导初始CD4+T淋巴细胞向Th22细胞分化，而转化生长因子-β(TGF-β)可抑制Th22细胞分化[6]。

人免疫缺陷病毒(HIV)、乙型肝炎病毒(HBV)和丙型肝炎病毒(HCV)等常见病毒引起的感染严重威胁人类的健康，病毒感染中的免疫学研究已成为人们关注的焦点之一。最近的研究表明，Th22细胞可能参与调节多种病毒性传染病的病理过程。本文就Th22细胞的特征、功能和分化机制及其在肝炎病毒、HIV等人类常见病毒感染中的最新研究进展作一综述。

1　Th22细胞的分子特征及功能

Th22细胞可分泌IL-22、IL-13、IL-26、TNF-α和颗粒酶B等，但不分泌IL-17、IFN-γ和IL-4[12,13]。通过活化转录因子芳香烃受体(AhR)可显著促进初始CD4+T淋巴细胞分化成Th22细胞[6,11,13]。Th22细胞在皮肤的表达量高于外周血，且表皮Th22细胞的数量比真皮更多，在表皮伤口愈合过程中发挥重要作用[11]。Th22细胞具有抗炎、抗菌及抗病毒等活性，在皮肤伤口愈合、自身免疫性疾病以及病毒感染性疾病中的重要作用均已得到证明[14,15,16]。

IL-22是Th22细胞的主要效应分子，属于IL-10家族，通过与其受体IL-22R结合发挥作用。IL-22R由IL-22R1(主要的高亲和力链)和IL-10R2(辅助受体链)亚基组成，IL-22R1主要在非造血组织(如皮肤、肺、肠以及胰腺等)表达，而在免疫细胞含量较高的组织(如胸腺、骨髓、脾脏等)不表达[17,18]。因此，IL-22对免疫细胞影响较少，主要作用于屏障表面细胞，如皮肤、呼吸系统、消化系统和关节等。还存在一种IL-22的可溶性受体，称IL-22BP或IL-22RA2，主要表达于肺、结肠以及乳房等组织，可阻断IL-22与IL-22R的结合，是IL-22的受体拮抗剂[19]。IL-22还可由其他淋巴系细胞，如Th17细胞、3型固有淋巴样细胞(ILC3)、真皮γδT细胞、分泌IL-17的CD8+(Tc17)细胞，非淋巴细胞系来源的巨噬细胞、中性粒细胞分泌[20,21,22,23]，甚至类风湿关节炎(RA)患者的成纤维细胞也可产生[22,24,25,26,27]。肠道中IL-22主要由ILC产生，在受到抗原等刺激后从黏膜相关淋巴组织迁移到固有层发挥作用[8]。γδT细胞是皮肤、肠道、肺、生殖道等上皮组织产生IL-22的主要来源，可在早期快速地对外来病原体做出反应，且IL-22在角质形成细胞、肠上皮细胞、支气管上皮细胞等人体不同部位可诱导不同的抗菌蛋白[28,29,30]。此外，IL-22可通过激活信号转导与转录激活因子3(STAT3)和细胞外调节蛋白激酶(ERK)通路直接作用于内皮细胞，刺激内皮细胞增殖、迁移，促进血管生成[30,31]。IL-22还可作用于结肠上皮下成纤维细胞(SEMFs)产生趋化因子、炎症因子和基质金属蛋白酶(MMPs)等炎症介质[30,32]。

IL-22与IL-22R的结合促进Jenus激酶(JAK)1和酪氨酸激酶(TYK)2磷酸化，进而活化其下游信号通路，包括丝裂原活化蛋白激酶(MAPK)通路(p38激酶、ERK1/2、MEK1/2以及JNK)、STAT3、STAT1、STAT5[33,34,35]。与IL-10家族的其他成员一样，IL-22主要通过激活Ser-727和Tyr-705促进STAT3磷酸化[17,36,37]。IL-22也有其独特性，IL-10诱导STAT3上酪氨酸残基磷酸化，而IL-22除诱导酪氨酸残基外还诱导丝氨酸残基的STAT3磷酸化，并激活ERK1/2通路[34]。这个差异有可能是因IL-22R1的区别所导致。SRC同源磷酸酶2(Shp2)与Tyr-251磷酸化残基的结合，Tyr-301活化的IL-22R1是激活STAT3所必需的，而STAT3的磷酸化是IL-22对上皮细胞发挥效应功能必不可少的[33,38,39]。IL-22还可诱导细胞因子信号转导1和3(SOCS1/3)抑制剂的表达，而SOCS1/3抑制剂反过来能抑制STAT3的活性[33]。IL-22还可激活PI3K-Akt-mTOR通路，促进肝细胞和结肠上皮细胞的迁移[33,40]。在RA中，IL-22通过调节p38MAPK/NF-κB和JAK2/STAT3信号诱导破骨细胞的形成[41]。

2　Th22细胞的分化

Th22细胞的分化受多种因素调节。单独的IL-6刺激可使初始CD4+T淋巴细胞向Th22细胞分化，而IL-6联合TNF-α可显著诱导Th22细胞的分化，但高剂量的TGF-β能抑制Th22细胞分化[6]。有学者对Th22细胞分化条件进行了优化处理，在抗IL-4/IFNγ存在情况下，联合IL-6、IL-23、IL-1β和芳香烃受体内源性配体(FICZ)4种因子进行处理时仍有IL-17A分泌，加入TGF-βR抑制剂可有效抑制IL-17A生成，但不影响IL-22的分泌，且可增加颗粒酶B和IL-13的表达水平[12,42]。IL-21和IL-23也可诱导Th22细胞分化，不论是单独的IL-21还是联合IL-1β或IL-23都能诱导Th22细胞分化和IL-22表达[42]。

研究显示，浆细胞样树突细胞(pDCs)比经典树突细胞(cDCs)能更强地诱导Th22细胞分化，pDCs和cDCs经活化后均可释放高浓度TNF-α和IL-6，当阻断TNF-α和IL-6后，Th22细胞分化被显著抑制，这提示DCs可能通过直接和间接两种方式促进Th22细胞分化[6]。微生物等外来抗原能激活DCs，释放TNF-α和IL-6，促进T细胞内AhR和IL-22因子表达，进而促进Th22细胞的分化[43]。人表皮和真皮的朗格汉斯细胞(LCs)也能诱导初始CD4+T淋巴细胞和外周血CD4+T淋巴细胞分化成Th22细胞，且表皮LCs比真皮LCs诱导能力强[44]。内源性的Toll-样受体4(TLR4)配体可刺激角化细胞分泌IL-23，与皮肤DCs上IL-23受体结合，激活内源性IL-23分泌，诱导初始CD4+T淋巴细胞向Th22细胞分化，并释放IL-22[45]。活化B细胞与初始CD4+T淋巴细胞在诱导Th17细胞分化的共培养条件下，可显著抑制CD4+T淋巴细胞内维甲酸相关孤核受体-γt(RORγt)的表达及IL-17的生成，同时明显影响Th22细胞分化和IL-22生成。进一步的体内实验表明，用活化B细胞注射治疗MRL/lpr狼疮小鼠模型后，抗-dsDNA抗体和尿蛋白水平降低，同时Th17细胞分化被抑制，而Th22细胞分化却得到增强[46]。

研究显示，当RORγt基因敲除时，初始CD4+T淋巴细胞表达IL-22减少，而T-bet基因敲除时IL-22表达显著增加[12]。抑制转录因子RUNX3表达后，Th22细胞的数量会显著下降[47]。抑制转录因子Bach2途径也可促进Th22细胞分化和IL-22表达[48]。醋酸甲羟孕酮(MPA)也可通过增强AhR信号促进Th22细胞应答，并降低Th1和Th17细胞表达，进而影响炎症性疾病及感染性疾病的易感性[49]。这些研究提示，AhR是Th22细胞分化的关键转录因子，转录因子RORγt和RUNX3是Th22细胞分化的正向调节因子，而T-bet和Bach2则是Th22细胞分化的负向调节因子。此外，Th22细胞在适当条件下可分化为Th1和Th2细胞。在体内IFNγ丰富的炎症微环境或在体外Th1促进条件下具有明显的可塑性，在体外Th2培养环境下，Th22细胞分泌IL-13增加[12]。由于Th17等细胞也会分泌IL-22，目前尚不清楚Th22细胞与Th17细胞间转化的条件[14]。因此Th22细胞的鉴定显得尤为重要，Mousset等[50]建议使用流式细胞仪鉴定Th22细胞时，可通过综合细胞表面标志物(CCR4+、CCR6+、CCR10+)，并结合细胞的转录因子(如AhR等)和/或细胞因子染色(IL-22+)来鉴定，并且要求IFN-γ-、IL-4-、IL-9-、IL-10-、IL-17-[50]。

3　Th22细胞在人类常见病毒感染中的作用

在人类病毒感染中，细胞免疫和体液免疫应答紊乱在其发生发展中起重要作用。除Th1、Th2、Th17、Tfh和Treg等Th细胞外，越来越多的研究发现，分泌IL-22的Th22细胞在多种病毒感染中发挥着关键作用[51,52]。

3.1　Th22细胞与HIV

研究发现，Th22细胞在HIV感染者的乙状结肠黏膜表达显著缺失，经长时间的抗逆转录病毒治疗后，可出现逆转[53]。循环Th22细胞表达HIV受体结合分子CCR5和α4β7，重组的IL-22可以抵抗HIV诱导的上皮细胞完整性破坏，在一些HIV抵抗的个体中，Th22细胞的数量明显高于健康对照及HIV感染者，这表明在HIV感染中，包括IL-22在内的一些蛋白分子参与了先天性的宿主抵抗机制[54,55]。在HIV感染的儿童和成人中，Th22细胞显著降低，而抗逆转录病毒药物成功治疗HIV感染者后，可见循环中Th22和Th17细胞随之显著增加，这表明循环中Th22和Th17细胞的增殖可为抑制HIV感染提供免疫学优势[56,57]。此外，在HIV感染者的黏膜组织中Th22细胞表达下降，Th22细胞通过CCR10/CCL28轴完成迁移，对黏膜起保护作用[58,59]。这些研究表明，Th22细胞在HIV感染中参与疾病的转归，发挥着重要的免疫保护作用。

3.2　Th22细胞与肝炎病毒

HBV感染是导致肝硬化和肝癌的主要因素。Th22细胞在HBV感染者血液中往往表现为数量的增加，同时IL-22的水平也明显升高，Th22细胞和IL-22水平与疾病的严重程度及预后相关[60,61,62,63,64]。注射IL-22可以促进HBV转基因小鼠肝脏炎症介质的表达，而不是直接抑制病毒的复制。中和IL-22不仅可减轻模型小鼠肝脏的损伤，而且显著抑制抗原非特异的炎症细胞向肝脏聚集，表明IL-22在HBV感染过程中发挥促进炎症反应的作用[63]。IL-22可以促进慢性乙型肝炎患者向肝细胞癌的快速进展，且肿瘤浸润的IL-22+细胞和血清中高水平的IL-22与肿瘤组织学分型和不良预后密切相关[65]。然而更多的研究提示，IL-22在肝脏损伤中起保护作用。在刀豆蛋白A(ConA)诱导的肝炎模型中，IL-22和IL-22R表达上升，IL-22中和抗体可以加重肝脏损伤，过表达IL-22可以活化STAT3，减少肝细胞凋亡[66]。在慢性HBV感染的患者和动物模型中，IL-22能通过活化STAT3通路，促进肝脏中肝干细胞/祖细胞(LPCs)的增殖[64]。Th22细胞及IL-22在HBV感染和肝损伤中的作用有待于进一步深入研究。

HCV可通过诱发肝脏炎症、氧化应激和肝细胞增殖反应导致肝脏代谢紊乱，加速向肝硬化和肝细胞癌转化[67,68,69]。研究显示，Th22细胞和IL-22在慢性HCV感染者的血液和肝脏中明显升高，而外周血总Notch信号蛋白的水平也显著升高，抑制Notch信号可降低HCV感染者中Th22细胞、IL-22和AhR的表达[70,71,72,73]。Th22细胞和IL-22在HCV感染相关的肝纤维化或肝硬化中发挥重要作用：一方面可以激活肝脏先天免疫，促进肝细胞增殖、迁移和再生，减少肝细胞凋亡，可能是治疗肝纤维化和肝细胞癌的一个有效靶点[68,69,73]，而IL-22BP是IL-22的竞争性抑制剂，IL-22BP过表达可加重肝纤维化和肝硬化的进展[73]；另一方面，肝内和外周血中高水平的IL-22+细胞和IL-22与肝纤维化的进展程度及α-平滑肌肌动蛋白(α-SMA)表达水平呈正相关，IL-22与IL-22R1结合可激活肝星状细胞(HSCs)，使细胞外基质(ECM)合成增加，进而加重HCV相关的肝纤维化[74]。IL-22体外刺激可促进HSCs增殖，加快HCV相关的原位肝移植术后复发(HCV-OLT)并进展至肝纤维化的速度[75]。这表明Th22细胞及IL-22在HCV感染和肝纤维化发展的过程中发挥关键作用，其详细机制有待于进一步研究。

3.3　Th22细胞与其他病毒

手足口病(HFMD)是由肠道病毒引起的感染性疾病，其中柯萨奇病毒A16型(CVA-16)和肠道病毒71型(EV-71)是最为常见的病原体。研究发现，在EV-71相关的重症和轻症患儿的外周血中，Th22细胞数量均显著高于健康对照组。IL-22、IL-17A、IL-23、IL-6、TNF-α、AhR和RORγt水平在轻症、重症和健康对照组间存在差异。而恢复期的患者，Th22细胞显著下降，可见Th22细胞在EV-71感染的病理过程中发挥重要作用[76]。IL-22在不同病原体感染的HFMD中可能呈现不同的作用，HFMD脑炎患者IL-5、IL-22和IL-23水平更高，且EV-71感染患者的IL-22水平高于CVA-16感染患者[77]。研究表明，在甲型流感病毒H3N2感染中，肺部IL-22因子和AhR基因表达及Th22细胞数量增加，且IL-22基因在Tαβ和Tγδ细胞中的转录增加，感染后IL-22BP基因在肺组织和肺淋巴细胞中的转录减少。在感染的亚致死阶段，IL-22可减弱肺部炎症，维持肺上皮的完整性，控制继发性细菌感染，然而其在致死阶段并不起重要作用[78,79]。这些研究表明，IL-22在流感病毒感染中参与肺损伤、修复和再生。此外，柯萨奇病毒B型(CVB3)诱导的病毒性心肌炎小鼠模型中，Th22细胞数量和IL-22水平均显著升高，而抗IL-22抗体治疗不仅加剧小鼠心肌的纤维化而且降低感染小鼠的生存率，这表明Th22细胞及IL-22在CVB3诱导的心肌炎小鼠模型中发挥着保护性作用[80,81](表1)。

点击查看表格
表1

Th22细胞在人类常见病毒感染中的作用

表1

Th22细胞在人类常见病毒感染中的作用

病毒或疾病IL-22表达水平Th22细胞相关分子作用参考文献
HIV下降CCR5、CCR10/CCL28表达上升保护黏膜组织，参与HIV抑制反应[53,54,55,58,59]
HBV上升STAT3、IL-22R表达上升抑制炎症反应，促进肝干细胞/祖细胞增殖，抑制肝细胞凋亡[63,64,66]
HCV上升IL-22BP, IL-22R, Notch表达上升促进早期炎症因子表达，活化肝星状细胞，促进肝硬化和肝纤维化[70,71,72,73]
HFMD上升AhR和RORγt表达上升与疾病的严重程度呈正相关[76,77]
H3N2上升AhR和RORγt表达上升降低肺部炎症，减少继发性细菌感染[78,79]
CVB3上升IL-22R表达上升加剧心肌纤维化，降低小鼠的生存率[80,81]

注：HIV.人免疫缺陷病毒；HBV.乙型肝炎病毒；HCV.丙型肝炎病毒；HFMD.手足口病；H3N2.甲型流感病毒H3N2亚型；CVB3.柯萨奇病毒B3型；IL-22.白细胞介素-22

4　总结与展望

Th22细胞的发现进一步丰富了CD4+T淋巴细胞免疫调节的网格系统，表明初始CD4+T淋巴细胞的高可塑性。IL-22是Th22细胞的主要效应细胞因子，AhR是Th22细胞分化的关键转录因子，IL-6、TNF-α和AhR激动剂及TGF-β1受体抑制剂可促进Th22细胞的分化，TGF-β1和IL-10可抑制Th22细胞的分化。在某些病毒疾病中，Th22细胞及其效应分子起保护作用，而在另一些病毒感染中，Th22细胞可加剧疾病进展。虽然对Th22细胞的研究已经扩展到不同的系统，但是对这种精确的调控机制的理解仍然非常有限。此外，Th22的细胞分化和下游信号途径仍未完全清楚。因此，进一步研究Th22细胞的分化和调控机制，探讨其与其他免疫细胞的相互作用，分析其在各种疾病中的作用机制，将为疾病的诊断和治疗提供新的策略。

利益冲突
利益冲突

所有作者均声明不存在利益冲突

参考文献
[1]
WangW, SungN, Gilman-SachsA, et al. T helper (Th) cell profiles in pregnancy and recurrent pregnancy losses: Th1/Th2/Th9/Th17/Th22/Tfh cells[J]. Front Immunol, 2020, 11: 2025. DOI: 10.3389/fimmu.2020.02025.
[2]
RuterbuschM, PrunerKB, ShehataL, et al. In vivo CD4(+) T cell differentiation and function: revisiting the Th1/Th2 paradigm[J]. Annu Rev Immunol, 2020, 38: 705-725. DOI: 10.1146/annurev-immunol-103019-085803.
[3]
ChatzileontiadouDSM, SloaneH, NguyenAT, et al. The many faces of CD4(+) T cells: immunological and structural characteristics[J]. Int J Mol Sci, 2020, 22(1): 73. DOI: 10.3390/ijms22010073.
[4]
GurneyAL. IL-22, a Th1 cytokine that targets the pancreas and select other peripheral tissues[J]. Int Immunopharmacol, 2004, 4(5): 669-677. DOI: 10.1016/j.intimp.2004.01.016.
[5]
ZhengY, DanilenkoDM, ValdezP, et al. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis[J]. Nature, 2007, 445(7128): 648-651. DOI: 10.1038/nature05505.
[6]
DuhenT, GeigerR, JarrossayD, et al. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells[J]. Nat Immunol, 2009, 10(8): 857-863. DOI: 10.1038/ni.1767.
[7]
DumoutierL, LouahedJ, RenauldJC. Cloning and characterization of IL-10-related T cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9[J]. J Immunol, 2000, 164(4): 1814-1819. DOI: 10.4049/jimmunol.164.4.1814.
[8]
XieMH, AggarwalS, HoWH, et al. Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R[J]. J Biol Chem, 2000, 275(40): 31335-31339. DOI: 10.1074/jbc.M005304200.
[9]
WolkK, SabatR. Interleukin-22: a novel T- and NK-cell derived cytokine that regulates the biology of tissue cells[J]. Cytokine Growth Factor Rev, 2006, 17(5): 367-380. DOI: 10.1016/j.cytogfr.2006.09.001.
[10]
KreymborgK, EtzenspergerR, DumoutierL, et al. IL-22 is expressed by Th17 cells in an IL-23-dependent fashion, but not required for the development of autoimmune encephalomyelitis[J]. J Immunol, 2007, 179(12): 8098-8104. DOI: 10.4049/jimmunol.179.12.8098.
[11]
EyerichS, EyerichK, PenninoD, et al. Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling[J]. J Clin Invest, 2009, 119(12): 3573-3585. DOI: 10.1172/JCI40202.
[12]
PlankMW, KaikoGE, MaltbyS, et al. Th22 cells form a distinct Th lineage from Th17 cellsin vitro with unique transcriptional properties and Tbet-dependent Th1 plasticity[J]. J Immunol, 2017, 198(5): 2182-2190. DOI: 10.4049/jimmunol.1601480.
[13]
TrifariS, KaplanCD, TranEH, et al. Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells[J]. Nat Immunol, 2009, 10(8): 864-871. DOI: 10.1038/ni.1770.
[14]
ZhangL, LiYG, LiYH, et al. Increased frequencies of Th22 cells as well as Th17 cells in the peripheral blood of patients with ankylosing spondylitis and rheumatoid arthritis[J/OL]. PLoS One, 2012, 7(4): e31000. DOI: 10.1371/journal.pone.0031000.
[15]
GittlerJK, ShemerA, Suarez-FarinasM, et al. Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis[J]. J Allergy Clin Immunol, 2012, 130(6): 1344-1354. DOI: 10.1016/j.jaci.2012.07.012.
[16]
NogralesKE, ZabaLC, ShemerA, et al. IL-22-producing " T22" T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells[J]. J Allergy Clin Immunol, 2009, 123(6): 1244-1252, e2. DOI: 10.1016/j.jaci.2009.03.041.
[17]
OuyangW, O’GarraA. IL-10 family cytokines IL-10 and IL-22: from basic science to clinical translation[J]. Immunity, 2019, 50(4): 871-891. DOI: 10.1016/j.immuni.2019.03.020.
[18]
WolkK, KunzS, WitteE, et al. IL-22 increases the innate immunity of tissues[J]. Immunity, 2004, 21(2): 241-254. DOI: 10.1016/j.immuni.2004.07.007.
[19]
XuW, PresnellSR, Parrish-NovakJ, et al. A soluble class II cytokine receptor, IL-22RA2, is a naturally occurring IL-22 antagonist[J]. Proc Natl Acad Sci U S A, 2001, 98(17): 9511-9516. DOI: 10.1073/pnas.171303198.
[20]
WolkK, KunzS, AsadullahK, et al. Cutting edge: immune cells as sources and targets of the IL-10 family members？[J]. J Immunol, 2002, 168(11): 5397-5402. DOI: 10.4049/jimmunol.168.11.5397.
[21]
HanssonM, SilverpilE, LindenA, et al. Interleukin-22 produced by alveolar macrophages during activation of the innate immune response[J]. Inflamm Res, 2013, 62(6): 561-569. DOI: 10.1007/s00011-013-0608-1.
[22]
ZindlCL, LaiJF, LeeYK, et al. IL-22-producing neutrophils contribute to antimicrobial defense and restitution of colonic epithelial integrity during colitis[J]. Proc Natl Acad Sci U S A, 2013, 110(31): 12768-12773. DOI: 10.1073/pnas.1300318110.
[23]
IkeuchiH, KuroiwaT, HiramatsuN, et al. Expression of interleukin-22 in rheumatoid arthritis: potential role as a proinflammatory cytokine[J]. Arthritis Rheum, 2005, 52(4): 1037-1046. DOI: 10.1002/art.20965.
[24]
SimonianPL, WehrmannF, RoarkCL, et al. Gammadelta T cells protect against lung fibrosis via IL-22[J]. J Exp Med, 2010, 207(10): 2239-2253. DOI: 10.1084/jem.20100061.
[25]
DudakovJA, HanashAM, van den BrinkMR. Interleukin-22: immunobiology and pathology[J]. Annu Rev Immunol, 2015, 33: 747-785. DOI: 10.1146/annurev-immunol-032414-112123.
[26]
CochezPM, MichielsC, HendrickxE, et al. AhR modulates the IL-22-producing cell proliferation/recruitment in imiquimod-induced psoriasis mouse model[J]. Eur J Immunol, 2016, 46(6): 1449-1459. DOI: 10.1002/eji.201546070.
[27]
MashikoS, BouguermouhS, RubioM, et al. Human mast cells are major IL-22 producers in patients with psoriasis and atopic dermatitis[J]. J Allergy Clin Immunol, 2015, 136(2): 351-359, e1. DOI: 10.1016/j.jaci.2015.01.033.
[28]
SteinbachS, VordermeierHM, JonesGJ. CD4+ and gammadelta T cells are the main producers of IL-22 and IL-17A in lymphocytes from Mycobacterium bovis-infected Cattle[J]. Sci Rep, 2016, 6: 29990. DOI: 10.1038/srep29990.
[29]
LuZ, LiuR, HuangE, et al. MicroRNAs: New regulators of IL-22[J]. Cell Immunol, 2016, 304-305: 1-8. DOI: 10.1016/j.cellimm.2016.05.003.
[30]
JiaL, WuC. The biology and functions of Th22 cells[J]. Adv Exp Med Biol, 2014, 841: 209-230.DOI: 10.1007/978-94-017-9487-9_8.
[31]
ProtopsaltisNJ, LiangW, NudlemanE, et al. Interleukin-22 promotes tumor angiogenesis[J]. Angiogenesis, 2019, 22(2): 311-323. DOI: 10.1007/s10456-018-9658-x.
[32]
AndohA, ZhangZ, InatomiO, et al. Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts[J]. Gastroenterology, 2005, 129(3): 969-984. DOI: 10.1053/j.gastro.2005.06.071.
[33]
LejeuneD, DumoutierL, ConstantinescuS, et al. Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from IL-10[J]. J Biol Chem, 2002, 277(37): 33676-33682. DOI: 10.1074/jbc.M204204200.
[34]
SonnenbergGF, FouserLA, ArtisD. Functional biology of the IL-22-IL-22R pathway in regulating immunity and inflammation at barrier surfaces[J]. Adv Immunol, 2010, 107: 1-29. DOI: 10.1016/B978-0-12-381300-8.00001-0.
[35]
ZhuJ, ZhouM, ZhaoX, et al. Blueberry, combined with probiotics, alleviates non-alcoholic fatty liver disease via IL-22-mediated JAK1/STAT3/BAX signaling[J]. Food Funct, 2018, 9(12): 6298-6306. DOI: 10.1039/c8fo01227j.
[36]
HeH, Guttman-YasskyE. JAK inhibitors for atopic dermatitis: an update[J]. Am J Clin Dermatol, 2019, 20(2): 181-192. DOI: 10.1007/s40257-018-0413-2.
[37]
CicciaF, GugginoG, RizzoA, et al. Interleukin (IL)-22 receptor 1 is over-expressed in primary Sjogren’s syndrome and Sjogren-associated non-Hodgkin lymphomas and is regulated by IL-18[J]. Clin Exp Immunol, 2015, 181(2): 219-229. DOI: 10.1111/cei.12643.
[38]
CheY, SuZ, XiaL. Effects of IL-22 on cardiovascular diseases[J]. Int Immunopharmacol, 2020, 81: 106277. DOI: 10.1016/j.intimp.2020.106277.
[39]
PickertG, NeufertC, LeppkesM, et al. STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing[J]. J Exp Med, 2009, 206(7): 1465-1472. DOI: 10.1084/jem.20082683.
[40]
DumoutierL, de MeesterC, TavernierJ, et al. New activation modus of STAT3: a tyrosine-less region of the interleukin-22 receptor recruits STAT3 by interacting with its coiled-coil domain[J]. J Biol Chem, 2009, 284(39): 26377-26384. DOI: 10.1074/jbc.M109.007955.
[41]
WenHY, LuoJ, LiXF, et al. 1, 25-Dihydroxyvitamin D3 modulates T cell differentiation and impacts on the production of cytokines from Chinese Han patients with early rheumatoid arthritis[J]. Immunol Res, 2019, 67(1): 48-57. DOI: 10.1007/s12026-018-9033-4.
[42]
YesteA, MascanfroniID, NadeauM, et al. IL-21 induces IL-22 production in CD4+ T cells[J]. Nat Commun, 2014, 5: 3753. DOI: 10.1038/ncomms4753.
[43]
Diaz-ZunigaJ, Melgar-RodriguezS, MonasterioG, et al. Differential human Th22-lymphocyte response triggered by Aggregatibacter actinomycetemcomitans serotypes[J]. Arch Oral Biol, 2017, 78: 26-33. DOI: 10.1016/j.archoralbio.2017.02.008.
[44]
FujitaH, NogralesKE, KikuchiT, et al. Human Langerhans cells induce distinct IL-22-producing CD4+ T cells lacking IL-17 production[J]. Proc Natl Acad Sci U S A, 2009, 106(51): 21795-21800. DOI: 10.1073/pnas.0911472106.
[45]
YoonJ, Leyva-CastilloJM, WangG, et al. IL-23 induced in keratinocytes by endogenous TLR4 ligands polarizes dendritic cells to drive IL-22 responses to skin immunization[J]. J Exp Med, 2016, 213(10): 2147-2166. DOI: 10.1084/jem.20150376.
[46]
YangJ, YangX, WangL, et al. B cells control lupus autoimmunity by inhibiting Th17 and promoting Th22 cells[J]. Cell Death Dis, 2020, 11(3): 164. DOI: 10.1038/s41419-020-2362-y.
[47]
FuD, SongX, HuH, et al. Downregulation of RUNX3 moderates the frequency of Th17 and Th22 cells in patients with psoriasis[J]. Mol Med Rep, 2016, 13(6): 4606-4612. DOI: 10.3892/mmr.2016.5108.
[48]
HuangR, ChenX, LongY, et al. MiR-31 promotes Th22 differentiation through targeting Bach2 in coronary heart disease[J]. Biosci Rep, 2019, 39(9): BSR20190986. DOI: 10.1042/BSR20190986.
[49]
PiccinniMP, LombardelliL, LogiodiceF, et al. Medroxyprogesterone acetate decreases Th1, Th17, and increases Th22 responses via AHR signaling which could affect susceptibility to infections and inflammatory disease[J]. Front Immunol, 2019, 10: 642. DOI: 10.3389/fimmu.2019.00642.
[50]
MoussetCM, HoboW, WoestenenkR, et al. Comprehensive phenotyping of T cells using flow cytometry[J]. Cytometry A, 2019, 95(6): 647-654. DOI: 10.1002/cyto.a.23724.
[51]
BenovaK, HanckovaM, KociK, et al. T cells and their function in the immune response to viruses[J]. Acta Virol, 2020, 64(2): 131-143. DOI: 10.4149/av_2020_203.
[52]
ShahSV, ManickamC, RamDR, et al. Innate lymphoid cells in HIV/SIV infections[J]. Front Immunol, 2017, 8: 1818. DOI: 10.3389/fimmu.2017.01818.
[53]
KimCJ, NazliA, RojasOL, et al. A role for mucosal IL-22 production and Th22 cells in HIV-associated mucosal immunopathogenesis[J]. Mucosal Immunol, 2012, 5(6): 670-680. DOI: 10.1038/mi.2012.72.
[54]
OliveiraLM, LimaJF, CervantesCA, et al. Increased frequency of circulating Tc22/Th22 cells and polyfunctional CD38(-) T cells in HIV-exposed uninfected subjects[J]. Sci Rep, 2015, 5: 13883. DOI: 10.1038/srep13883.
[55]
MisseD, YsselH, TrabattoniD, et al. IL-22 participates in an innate anti-HIV-1 host-resistance network through acute-phase protein induction[J]. J Immunol, 2007, 178(1): 407-415. DOI: 10.4049/jimmunol.178.1.407.
[56]
KhaitanA, KilbergM, KravietzA, et al. HIV-infected children have lower frequencies of CD8+ mucosal-associated invariant T (MAIT) cells that correlate with innate, Th17 and Th22 cell subsets[J/OL]. PLoS One, 2016, 11(8): e0161786. DOI: 10.1371/journal.pone.0161786.
[57]
陈川铁，赵方，杨桂林，等. 艾滋病患者抗反转录病毒治疗后外周血辅助性和调节性T淋巴细胞的变化及意义[J]. 中华传染病杂志，2015, 33(1)：25-29. DOI: 10.3760/cma.j.issn.1000-6680.
ChenCT, ZhaoF, YangGL, et al. Variation and significance of helper T cells and regulatory T cells in the peripheral blood before and after antiretroviral treatment of human immunodeficiency virus-1 infected patients[J]. Chin J Infect Dis, 2015, 33(1): 25-29. DOI: 10.3760/cma.j.issn.1000-6680.(in Chinese)
[58]
KimCJ, RousseauR, HuibnerS, et al. Impact of intensified antiretroviral therapy during early HIV infection on gut immunology and inflammatory blood biomarkers[J]. AIDS, 2017, 31(11): 1529-1534. DOI: 10.1097/QAD.0000000000001515.
[59]
NayracM, RequenaM, LoiseauC, et al. Th22 cells are efficiently recruited in the gut by CCL28 as an alternative to CCL20 but do not compensate for the loss of Th17 cells in treated HIV-1-infected individuals[J]. Mucosal Immunol, 2021, 14(1): 219-228. DOI: 10.1038/s41385-020-0286-6.
[60]
邹美银，汪美华，章幼奕，等. 慢性乙型肝炎患者外周血Th22细胞检测及其临床意义[J]. 中华临床医师杂志(电子版), 2014，8(7)：1221-1224. DOI: 10.3877/cma.j.issn.1674-0785.
ZouMY, WangMH, ZhangYY, et al. Determination of peripheral Th22 cells and its significance in patients with chronic hepatitis B[J]. Chin J Clinicaians (Electronic Edition), 2014, 8(7): 1221-1224. DOI: 10.3877/cma.j.issn.1674-0785.(in Chinese)
[61]
MoR, WangP, LaiR, et al. Persistently elevated circulating Th22 reversely correlates with prognosis in HBV-related acute-on-chronic liver failure[J]. J Gastroenterol Hepatol, 2017, 32(3): 677-686. DOI: 10.1111/jgh.13537.
[62]
CobleighMA, RobekMD. Protective and pathological properties of IL-22 in liver disease: implications for viral hepatitis[J]. Am J Pathol, 2013, 182(1): 21-28. DOI: 10.1016/j.ajpath.2012.08.043.
[63]
ZhangY, CobleighMA, LianJQ, et al. A proinflammatory role for interleukin-22 in the immune response to hepatitis B virus[J]. Gastroenterology, 2011, 141(5): 1897-1906. DOI: 10.1053/j.gastro.2011.06.051.
[64]
FengD, KongX, WengH, et al. Interleukin-22 promotes proliferation of liver stem/progenitor cells in mice and patients with chronic hepatitis B virus infection[J]. Gastroenterology, 2012, 143(1): 188-198, e7. DOI: 10.1053/j.gastro.2012.03.044.
[65]
ShiJ, WangY, WangF, et al. Interleukin 22 is related to development and poor prognosis of hepatocellular carcinoma[J]. Clin Res Hepatol Gastroenterol, 2020, 44(6): 855-864. DOI: 10.1016/j.clinre.2020.01.009.
[66]
RadaevaS, SunR, PanHN, et al. Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation[J]. Hepatology, 2004, 39(5): 1332-1342. DOI: 10.1002/hep.20184.
[67]
GoossensN, HoshidaY. Hepatitis C virus-induced hepatocellular carcinoma[J]. Clin Mol Hepatol, 2015, 21(2): 105-114. DOI: 10.3350/cmh.2015.21.2.105.
[68]
ReshamS, SaalimM, ManzoorS, et al. Mechanistic study of interaction between IL-22 and HCV core protein in the development of hepatocellular carcinoma among liver transplant recipients[J]. Microb Pathog, 2020, 142: 104071. DOI: 10.1016/j.micpath.2020.104071.
[69]
SaalimM, ReshamS, ManzoorS, et al. IL-22: a promising candidate to inhibit viral-induced liver disease progression and hepatocellular carcinoma[J]. Tumour Biol, 2016, 37(1): 105-114. DOI: 10.1007/s13277-015-4294-1.
[70]
GaoY, RenH, MengF, et al. Pathological roles of interleukin-22 in the development of recurrent hepatitis C after liver transplantation[J/OL]. PLoS One, 2016, 11(4): e0154419. DOI: 10.1371/journal.pone.0154419.
[71]
ZhangM, ZhangL, LiH, et al. Circulating T follicular helper cells are associated with rapid virological response in chronic hepatitis C patients undergoing peginterferon therapy[J]. Int Immunopharmacol, 2016, 34: 235-243. DOI: 10.1016/j.intimp.2016.03.005.
[72]
WuY, MinJ, GeC, et al. Interleukin 22 in liver injury, inflammation and cancer[J]. Int J Biol Sci, 2020, 16(13): 2405-2413. DOI: 10.7150/ijbs.38925.
[73]
JiangBC, LiuX, LiuXH, et al. Notch signaling regulates circulating T Helper 22 cells in patients with chronic hepatitis C[J]. Viral Immunol, 2017, 30(7): 522-532. DOI: 10.1089/vim.2017.0007.
[74]
SertorioM, HouX, CarmoRF, et al. IL-22 and IL-22 binding protein (IL-22BP) regulate fibrosis and cirrhosis in hepatitis C virus and schistosome infections[J]. Hepatology, 2015, 61(4): 1321-1331. DOI: 10.1002/hep.27629.
[75]
WuLY, LiuS, LiuY, et al. Up-regulation of interleukin-22 mediates liver fibrosis via activating hepatic stellate cells in patients with hepatitis C[J]. Clin Immunol, 2015, 158(1): 77-87. DOI: 10.1016/j.clim.2015.03.003.
[76]
CuiD, ZhongF, LinJ, et al. Changes of circulating Th22 cells in children with hand, foot, and mouth disease caused by enterovirus 71 infection[J]. Oncotarget, 2017, 8(17): 29370-29382. DOI: 10.18632/oncotarget.14083.
[77]
ZhangSY, XuMY, XuHM, et al. Immunologic characterization of cytokine responses to enterovirus 71 and coxsackievirus A16 infection in children[J]. Medicine, 2015, 94(27): e1137. DOI: 10.1097/MD.0000000000001137.
[78]
GeorgelAF, CayetD, PizzornoA, et al. Toll-like receptor 5 agonist flagellin reduces influenza A virus replication independently of type I interferon and interleukin 22 and improves antiviral efficacy of oseltamivir[J]. Antiviral Res, 2019, 168: 28-35. DOI: 10.1016/j.antiviral.2019.05.002.
[79]
IvanovS, RennesonJ, FontaineJ, et al. Interleukin-22 reduces lung inflammation during influenza A virus infection and protects against secondary bacterial infection[J]. J Virol, 2013, 87(12): 6911-6924. DOI: 10.1128/JVI.02943-12.
[80]
KongQ, WuW, YangF, et al. Increased expressions of IL-22 and Th22 cells in the coxsackievirus B3-induced mice acute viral myocarditis[J]. Virol J, 2012, 9: 232. DOI: 10.1186/1743-422X-9-232.
[81]
GuoY, WuW, CenZ, et al. IL-22-producing Th22 cells play a protective role inCVB3-induced chronic myocarditis and dilated cardiomyopathy by inhibiting myocardial fibrosis[J]. Virol J, 2014, 11: 230. DOI: 10.1186/s12985-014-0230-z.
　
　
展开/关闭提纲
查看图表详情
回到顶部
放大字体
缩小字体
标签
关键词
辅助诱导T淋巴细胞
传染病
病毒
Th22细胞
IL-22
肝纤维化
病毒感染
受体肿瘤坏死因子
CD4T淋巴细胞
Th17细胞