Research progress on the role of G-protein-coupled receptors in T lymphocyte immunomodulation
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摘要: G蛋白偶联受体(GPCRs)是一类跨膜受体超家族，参与多种信号转导通路，在细胞迁移、代谢等生理过程中发挥重要功能。T淋巴细胞是重要的免疫细胞，参与炎症反应过程并在细胞免疫中发挥重要作用。目前已发现多种GPCRs在T淋巴细胞中表达并参与T淋巴细胞免疫调节过程，本文将对GPCRs在T淋巴细胞免疫调节中的作用进行综述。Abstract: G-protein-coupled receptors (GPCRs) are a type of superfamily of transmembrane receptors, involved in multiple signaling pathways, and playing an important role in physiological processes such as cell migration and metabolism. T lymphocytes are important immune cells that participate in the inflammatory process and play an important role cellular immunity. To date, multiple GPCRs have been found to be expressed in T lymphocytes and participate in T cell immunomodulatory processes. This paper reviews the role of GPCRs in T lymphocyte immunomodulation.
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Keywords:
- G-protein-coupled receptors /
- T lymphocytes /
- immunity /
- tuberculosis
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G蛋白偶联受体(G-protein-coupled receptors, GPCRs)是一类膜蛋白受体的总称，是人体内最大的膜受体蛋白家族。GPCRs可结合多种细胞外信号，通过激活G蛋白将细胞外信号传递到细胞内部，在调节机体生理功能中起到重要作用，并在其发挥作用的过程中受到多种分子的调控[1-4]。GPCRs是药物研发的重要靶点之一，尤其是对心血管、神经、免疫等相关疾病的药物研发。目前靶向GPCRs的药物约500个，占美国食品药品监督管理局(U.S. Food and Drug Administration, FDA)已批准药物的34%，占全球市场的27%[5-9]。
T淋巴细胞(简称T细胞)在细胞免疫中起重要作用，T细胞功能紊乱可引起多种疾病，如感染、过敏等。目前在T细胞表面已经发现了多种GPCRs，其中许多都参与了T细胞活化、迁移和细胞周期调控并发挥关键作用。
T细胞来源于骨髓的淋巴干细胞，在胸腺中分化、发育成熟，通过淋巴和血液循环分布于全身的免疫器官和组织。受到刺激后，细胞外信号分子通过多种信号通路介导效应T细胞活化，活化后的CD4+T细胞分化为不同的效应T细胞亚群，产生多种细胞因子。研究[10-11]发现，CD4+T细胞亚群Th1和Th2可释放白细胞介素(interleukin, IL)-1、IL-2、IL-4、IL-5、IL-6、肿瘤坏死因子(tumor necrosis factor, TNF)-α、TNF-β、干扰素γ等多种炎性因子促进T细胞介导的炎症反应。活化后的CD8+T细胞通过穿孔蛋白和Fas配体(Fas ligand, FasL)杀伤靶细胞。研究[12]发现，GPCRs及其信号通路在T细胞免疫过程中起着重要作用，如参与T细胞的激活，维持细胞稳态，参与细胞代谢。
1. GPCRs信号
GPCRs包含7个跨膜蛋白受体超家族，可与离子、神经递质和趋化因子等多种细胞外配体进行结合，并通过与三磷酸鸟苷(guanosine triphosphate, GTP)相互作用进一步激活细胞膜上的G蛋白。G蛋白由α、β和γ三个亚基组成，根据α亚基的不同，G蛋白进一步分为四个不同的亚家族：Gs, Gi/o, Gq/11和G12/13。在静息状态下，α亚基及β、γ亚基与二磷酸鸟苷(guanosine diphosphate, GDP)结合。当GPCRs被激活后，GTP结合G蛋白的α亚基，引起α亚基与β、γ亚基分离，与下游信号分子相互作用，调节细胞功能[13]。GPCRs与Gs结合后激活腺苷酸环化酶，升高细胞内环磷酸腺苷(cyclic adenosine monophosphate, cAMP)水平。GPCRs与Gi结合可抑制腺苷酸环化酶活性，细胞内cAMP水平降低。GPCRs与Gs结合后可激活磷脂酶C，磷脂酶C可以将磷脂酰肌醇二磷酸[phosphatidylinositol(4, 5)bisphosphate, PIP2]转化为二酰基甘油酯(diacylglycerol, DAG)，进而激活蛋白激酶C(protein kinase C, PKC)，介导钙离子释放。同时，GPCRs信号还可以受到G蛋白信号传导调节蛋白(regulators of G protein signaling, RGS proteins)、GPCRs激酶(G protein-coupled receptor kinases, GRKs)和β-阻滞蛋白(β-arrestin)等调节[14]。在T细胞表面已经发现了多种GPCRs，下面将列出一些与T细胞功能与调节相关的典型GPCRs。
2. GPCRs可调节T细胞迁移
2.1 C-C趋化因子受体(chemokine receptor, CCR)5
CCR5是GPCRs家族中的一种细胞膜蛋白，可在T细胞、巨噬细胞及小胶质细胞表面表达，结合CCL3、CCL4及CCL5，是T细胞活化和动员的重要调节剂，可参与T细胞向感染部位的迁移[15-17]。Hoft等[16]研究表明，CCR5与配体结合后可促进Th1细胞迁移至小鼠的结核分枝杆菌感染的部位。Harlin等[18]发现，小鼠黑色素瘤部位CD8+T细胞CCR5表达水平升高；当缺乏CCR5配体时，黑色素瘤小鼠体内T细胞在肿瘤部位浸润减少。Tan等[19]发现调节性T细胞(regulatory T cells, Treg)可迁移到肿瘤微环境，这一过程是由CCL5-CCR5轴介导，当CCR5抑制剂存在时，Treg细胞的迁移减少。Tavares等[20]研究表明小鼠感染甲型流感病毒后，体内释放炎症因子，信号分子通过CCR5通路诱导T细胞募集到感染部位，进而形成支气管相关淋巴组织(inducible bronchus-associated lymphoid tissue, iBALT)，减少体内病毒量并改善肺功能；而CCR5敲除小鼠体内的T细胞募集数量较少，肺损伤及肺功能障碍程度较重，导致感染流感病毒后的病死率较高。CCR5还参与呼吸道病毒感染期间记忆性CD8+T细胞向肺气道的迁移[21]。此外，CCR5可与CXCR4相互作用，调节T细胞的活化[22]。
2.2 GPR56
GPR56是一种黏附型GPCRs(adhesion G protein-coupled receptors, aGPCRs)，细胞外N端结构域包含较多的丝氨酸和苏氨酸残基以及GPCRs蛋白水解位点(GPCRs proteolysis site, GPS)结构域，这些结构在介导细胞功能时起到重要作用。Peng等[23]研究发现，在巨细胞病毒感染期间，体内效应CD8+T细胞稳定表达GPR56，并且GPR56与细胞毒性T细胞(cytotoxic T lymphocyte, CTL)的迁移有关，与对照组相比，GPR56表达上调可抑制T细胞迁移。此外，Liu等[24]研究表明，GPR56信号通路与CTL发挥毒性功能有关，GPR56可成为鉴别T细胞的标志物。
2.3 趋化因子受体(CXCR)3
CXCR3是GPCRs家族中的一员，可在Th1细胞及CTL细胞表面表达，与趋化因子配体(CXCL)9、CXCL10和CXCL11等结合。CXCR3与配体结合后可引起多种细胞反应，在调节T细胞迁移过程中发挥重要作用[25-26]。Li等[27]发现，与野生型小鼠相比，CXCR3-/-小鼠在肝移植切口处Tregs细胞的动员和募集较少，而CXCL10/CXCR3信号通路激活可促进肝移植切口处Tregs的动员。Kuo等[28]发现CXCR3信号通路介导的T细胞募集可导致皮肤移植排斥，CXCR3与配体结合后促进T细胞的浸润，使供体发生皮肤移植排斥反应。CXCR3除了参与T细胞募集与迁移外，还参与T细胞的分化。Karin等[29]发现，CXCL10与CXCR3结合后，可介导STAT1、STAT4和STAT5等磷酸化，STAT1与STAT6磷酸化后可引起T细胞分化为Th1细胞。CXCL11与CXCR3结合后，通过mTOR通路参与CD4+T细胞分化，形成分泌IL-10的Tr1。此外，有研究[30]发现CXCR3缺陷的CD8+T终末分化水平较低。
2.4 CCR4
CCR4是GPCRs家族的一员，CCR4的配体包括CCL17和CCL22[31-32]，CCR4在T细胞的迁移中起着重要作用。一项小鼠相关研究[12]发现，树突状细胞活化后可激活T细胞，促进T细胞表达CCR4，与对照组相比，被激活的CCR4缺陷T细胞迁移至肺部的数量明显减少，树突状细胞可通过诱导T细胞表面CCR4表达，进而促进T细胞迁移至肺。调控Th17细胞的CCR4/TARC信号轴可介导T细胞向肺内的迁移[33]。因此，利用CCR4抗体阻断趋化因子与CCR4的结合，抑制Th2细胞向炎症部位迁移，是控制变态反应的新靶点。CCR4在肿瘤患者体内T细胞表面高表达[34]，CCR4的高表达与肿瘤性疾病的高风险进展相关[35]，并且CCR4+T细胞的数量在皮肤T细胞淋巴瘤的病情后期扩散时明显增加[36]。CCR4还与多种过敏性炎症疾病有关，如哮喘、特应性皮炎和变应性鼻炎[37]，Honjo等[38]研究表明，在过敏性肺炎的小鼠模型中，CCR4为抗原特异性Th2细胞进入肺和气道所必需，机体处于炎症感染时，CCR4+CD4+T细胞的聚集可被CCR4抗体K327明显抑制，且其抑制作用与剂量呈正相关，因此，CCR4可作为临床治疗AR的新靶点[39]。
2.5 CCR7
CCR7属于GPCRs家族，可在T细胞表面表达，介导T细胞迁移[40]。配体CCL19、CCL21与CCR7结合后可介导细胞外信号传导[41-43]。在小鼠试验中，CCR7是CD4+T细胞迁移至淋巴组织的重要受体[44]，敲除CCR7后的T细胞不能迁移至淋巴结[45]。此外，在适应性免疫中，次级淋巴组织(secondary lymphoid tissues, SLTs)内CCR7介导的T细胞迁移发挥重要作用[46]。含有SH2结构的5’肌醇磷酸酶-1(SH2-containing inositol phosphatase-1, SHIP-1)表达上调可促进CD4+T细胞表面CCR7表达，进而促进CCR7介导的T细胞向局部淋巴结的转移，拮抗细胞SHIP-1表达可抑制此迁移过程[47]，表明CCR7在T细胞迁移过程中发挥重要作用。CCR7在免疫系统疾病中也发挥重要作用。原发性干燥综合征(primary Sjogren’s syndrome, pSS)患者体内T细胞表达CCR7明显上调，加入CCR7抗体后，pSS患者的CD4+T细胞迁移能力明显下降，表明CCR7是T细胞迁移的重要因素。T细胞表面的CCL21/CCR7被活化后可激活细胞内JNK和p38MAPK通路，阻断两条通路后，pSS患者体内CD4+T细胞的迁移明显减少，提示JNK和p38MAPK通路在pSS患者体内CD4+T细胞的迁移过程中发挥重要作用，是治疗pSS的新靶点。免疫组化结果显示，在皮肌炎(dermatomyositis, DM)患者的炎症浸润部位，CCR7表达明显升高[48]。此外，在DM患者的肌肉组织匀浆中，CCR7的表达显著上调，表明CCR7可能参与了DM患者炎性T细胞的募集[49]。
3. GPCRs可调节T细胞分化
3.1 嘌呤受体P2Y6(purinergic receptor P2Y, G protein-coupled, 6)受体
P2Y6受体属于GPCRs中的P2受体家族，可被细胞外核苷酸激活，在调节T细胞对炎症的反应中起着重要作用，P2Y6受体参与包括气道炎症反应在内的多种炎症反应[50]。研究[51-52]表明，在细菌和病毒诱导的机体免疫反应中，P2Y6受体发挥重要作用。此外，P2Y6受体在T细胞活化中发挥作用，P2Y6表达可抑制效应T细胞的活化[53-55]。
3.2 G2A
G2A是GPCRs家族的一员，可在淋巴细胞和巨噬细胞表面表达。G2A的配体包括溶血磷脂酰胆碱(lyso-phosphatidylcholine, LPC)。LPC是一种促炎脂质，可激活G2A，诱导T细胞募集到炎症部位[56-57]，此外，有研究[56-60]发现，LPC通过G2A可激活ERK1/2、JNK、MAPK等下游信号分子，进而通过升高TGF-β1表达水平促进Tregs功能，其中JNK是LPC诱导nTregs中TGF-β1表达的主要因素。G2A与LPC结合后能够调节T细胞迁移，还参与自身抗原特异性T细胞的迁移，介导慢性自身免疫性疾病的发展；另一方面，G2A可负责调节T细胞对抗原的特异性反应，通过减少自身抗原特异性T细胞的产生来减弱免疫反应。G2A在T细胞自身免疫性疾病中的作用还需要进一步研究。
3.3 EP
EP是位于细胞膜的GPCRs家族成员之一，可与前列腺素E2(prostaglandin E2, PGE2)结合。EP分为EP1、EP2、EP3和EP4四种不同亚型，参与不同的信号传导途径，调节免疫反应，发挥生理功能[61]。EP1与Gq结合后可被激活，升高Treg细胞内PGE蛋白及钙水平，激活PKC，进而激活NFAT/NFκB/MAPK信号通路，诱导基因转录，发挥生理功能[62]。EP受体可调节T细胞介导的免疫反应。Li等[62]发现PGE结合EP2后可通过cAMP通路降低Foxp3 mRNA表达水平，进而抑制T细胞分化。Nataraj等[63]发现激活EP1可增强Th1介导的免疫反应。Boniface等[64]发现PGE结合EP2、EP4后可通过cAMP通路活化Th17细胞。Sreeramkumar等[65]发现EP4在Th1细胞活化过程中表达水平明显升高，抑制CD4+T细胞表面的EP受体会减少炎症期间CD4+T细胞向炎症部位迁移，减少CD4+T细胞的增殖。
3.4 G蛋白偶联受体激酶(GRK)2
GRK2属于GPCRs家族成员，在T细胞表面表达，并在介导内吞、细胞内运输、机体脱敏等过程中起重要作用[66]。研究[67]表明，GRK2可通过磷脂酰肌醇-3-激酶(phosphatidylinositol-3-kinase, PI3K)、AKT、丝裂原活化蛋白(mitogen-activated protein, MEK)等通路介导炎症、心血管和肿瘤等疾病的进展。此外，GRK2在T细胞中的表达与哮喘发病有关，有研究[68]发现GRK2可激活T细胞受体(T cell receptor, TCR)信号，促进IL-2和IL-10等细胞因子的产生。GRK2在哮喘患者体内和暴露于屋尘螨(HDM)的小鼠的肺内表达增强。在HDM诱导的小鼠过敏性哮喘模型中发现，与对照组相比，敲除T细胞表面GRK2受体的小鼠体内IL-4、IL-13水平降低，支气管肺泡灌洗液(BALF)淋巴细胞计数和黏液分泌明显减少，肺部炎症加重，提示GRK2在哮喘相关T细胞活化中发挥重要作用[69]。此外，GRK2可通过介导PI3K-AKT通路调节Tregs分化及发挥功能[70-71]。研究[68]表明GRK2参与TCR激活CXCR4，并介导CXCR4的磷酸化，进而促进TCR-CXCR4复合物形成。此外，TCR介导的Src激酶激活可能导致GRK2磷酸化，从而影响T细胞活化。
4. GPCRs可调节T细胞代谢
4.1 腺苷A2A受体(A2AR)
T细胞表面可表达A2AR。A2AR结合腺苷分子，参与细胞信号传导，是炎症和免疫应答的重要受体[72-73]。CD8+T细胞可通过A2AR信号传导通路抑制T细胞的效应功能，如抑制T细胞增殖、活化，并且抑制T细胞分泌促炎因子(IFNγ、TNFα)。A2AR可结合Gs蛋白，增加cAMP和蛋白激酶A(protein kinase A, PKA)水平，通过细胞内A2AR/PKA/mTORC1信号通路抑制T细胞活化，引起T细胞代谢障碍。此外，A2AR激动剂可减少CD8+T细胞IFN-γ的产生[74-77]。Mastelic-Gavillet等[78]发现，腺苷与A2AR结合后，可降低CD8+T细胞的糖酵解代谢活性，损伤CD8+T细胞活性，相反，当选择性抑制A2AR后，由腺苷引起的CD8+T细胞损伤减少。
4.2 GPR30
GPR30是GPCRs家族中的一员，分布于细胞膜及内质网，在多种组织和细胞中表达，调节机体骨骼发育、生殖等生理功能。GPR30结合雌激素后可升高细胞内Ca2+浓度，诱导细胞核合成磷脂酰肌醇3, 4, 5-三磷酸(phosphatidylinositol 3, 4, 5-trisphosphate, PIP3)，参与细胞的存活、增殖过程[79-80]。Prossnitz等[81]发现，雌激素可通过结合GPR30调节CD4+T细胞的免疫功能，GPR30特异性激动剂G-1可增强T细胞的免疫抑制，促进细胞凋亡，抑制炎症因子的产生。Wang等[82]发现GPR30敲除小鼠可消除体内雌激素诱导的脾细胞CD4+FoxP3+Treg中程序性死亡受体(programmed cell death protein, PD)-1表达上调，在Treg细胞中雌激素通过GPR30和PD-1介导的机制增强Treg细胞的抑制活性。研究[83]发现，长期雌激素治疗会导致胸腺萎缩及胸腺细胞功能丧失，Wang等[84]发现雌激素可通过GPR30介导胸腺萎缩，在E2诱导的胸腺萎缩模型中，GPR30敲除小鼠的胸腺萎缩程度比对照组明显降低，GPR30激动剂可诱导胸腺萎缩和胸腺细胞凋亡。
5. GPCRs与感染
GPCRs在调节T细胞功能中起到重要作用，而T细胞作为免疫细胞的重要组成部分，在机体感染病原体过程中发挥作用。Fisher等[85]发现，恙虫病感染期间鼠脑组织的差异基因表达分析发现T细胞中CXCR3基因表达较对照组明显升高。GPCRs在结核分枝杆菌感染过程中也发挥重要作用。Mamtani等[86]发现，CCR5及其配体的促炎作用与活动性结核病发展密切相关。Shanmugasundaram等[87]发现结核分枝杆菌潜伏感染者气道内的大部分特异性CD4+T细胞表达CXCR3，且患者肺部的CXCR3+CD4+T细胞数量与结核分枝杆菌浓度呈负相关。Park等[88]发现，经结核分枝杆菌的RpfE蛋白刺激后的树突状细胞可产生PGE2，产生的PGE2主要通过EP4受体诱导Th1和Th17细胞分化，进而发挥较强的抗结核分枝杆菌活性。GPCRs也参与病毒感染后引起的免疫反应。Kuo等[25]发现，当单纯疱疹病毒感染皮肤后，CD8+T细胞表面CXCR3表达上调，且CXCR3的配体CXCL9、CXCL10水平高于对照组皮肤细胞，CXCR3与配体结合后可促进CD8+T细胞募集到感染部位，有助于清除病毒。当皮肤感染牛痘病毒时，表达CXCR3的CD8+T细胞迁移至牛痘病毒感染部位，发挥细胞杀伤作用。此外，CCR1可调节EB病毒(Epstein-Barr virus, EBV)基因表达水平、癌细胞播散和T细胞迁移[89]。因此，在自然杀伤/T细胞淋巴瘤(natural killer/T-cell lymphoma, NKTCL)中，靶向CCR1的治疗有助于EBV清除、T细胞活化和淋巴瘤细胞杀伤，是治疗EBV诱导癌症的新方向。GPCRs在人类免疫缺陷病毒(human immunodeficiency virus, HIV)感染机体过程中也发挥作用。CCR5和CXCR4能够直接与HIV表面糖蛋白GPl20结合，促进HIV-1病毒进入T细胞，是HIV-1和HIV-2病毒入侵细胞的关键步骤。配体CCL5、CXCL12分别与CCR5、CXCR4结合后可抑制HIV-1感染机体过程[90]。目前，使用CXCR4和CCR5拮抗剂治疗HIV在临床研究方面已取得一定成果。组织驻留记忆(tissue-resident memory, TRM)细胞促炎活性较强，在急性感染期间，TGF-β诱导GPR56在TRM细胞表达上调，抑制TRM细胞的活性，避免炎症引起的机体损伤。此外，在淋巴细胞性脉络丛脑膜炎病毒(lymphocytic choriomeningitis virus, LCMV)和李斯特菌急性感染时，GPR56在CD8+TRM细胞中特异性上调[91]，调节CD8+T细胞的分化及功能。在流行性感冒病毒感染期间，气道炎性上皮分泌的CXCL9和CXCL10增加，募集表达CXCR3趋化因子受体的CD8+T细胞[92]。综上所述，GPCRs在病毒感染过程中发挥重要作用，探究在病毒感染过程起关键作用的GPCRs可为病毒药物的研发提供新的靶点[93]。
T细胞中的GPCRs的功能见图 1，GPCRs在T细胞中的作用见图 2。
图 1 T细胞中GPCRs的功能
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图 2 GPCRs在T细胞中的作用下载:
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6. 总结与展望
综上所述，T细胞参与多种适应性免疫反应，T细胞功能紊乱与自身免疫性疾病有关。GPCRs及其调控分子在T细胞生物学功能中起着重要作用。本文列出了一些参与调节T细胞功能的GPCRs信号通路及其调控因子，以及在T细胞发挥功能的过程中GPCRs介导的信号通路成分。未来对这些分子的研究将会给T细胞生物学提供新视野。此外，GPCRs及其配体与感染性疾病的发展之间密切相关，进一步研究可为疾病治疗提供重要的药理靶点。
利益冲突：所有作者均声明不存在利益冲突。
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图 1 T细胞中GPCRs的功能
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图 2 GPCRs在T细胞中的作用
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