張奕+張?zhí)m英+歐陽(yáng)瑤
[摘要] 具有促炎作用的輔助性T細(xì)胞17(Th17)及維持免疫耐受的調(diào)節(jié)性T細(xì)胞(Treg)是體內(nèi)重要的兩種免疫細(xì)胞,在分化上關(guān)系密切且功能上相互制約,存在一種動(dòng)態(tài)平衡。兩者失衡會(huì)導(dǎo)致自身免疫性疾病、慢性感染疾病、腫瘤。近年來(lái)隨著呼吸系統(tǒng)常見(jiàn)疾病的不斷深入研究,發(fā)現(xiàn)Th17細(xì)胞、Treg細(xì)胞與肺部疾病的發(fā)病機(jī)制有關(guān),Th17/Treg失衡參與了慢性阻塞性肺疾病、肺癌、肺結(jié)節(jié)病及哮喘的免疫調(diào)節(jié)機(jī)制。本文闡述了Th17細(xì)胞、Treg細(xì)胞以及Th17/Treg失衡在上述肺部相關(guān)疾病中的研究進(jìn)展。
[關(guān)鍵詞] 輔助性T細(xì)胞17;調(diào)節(jié)性T細(xì)胞;肺部疾??;研究進(jìn)展
[中圖分類(lèi)號(hào)] R56 [文獻(xiàn)標(biāo)識(shí)碼] A [文章編號(hào)] 1673-7210(2017)12(b)-0020-05
[Abstract] T helper 17 cells (Th17) with pro-inflammatory activity and regulatory T cells (Treg) cells that maintain immune tolerance are important immune cells in humans. They are closely related in differentiation and functional constraints to each other, and there is a dynamic balance. Imbalance between the two can lead to autoimmune diseases, tumors, persistent infection diseases. In recent years, with the study of the common diseases of the respiratory system deeply, of Th17 cells and Treg cells were found to be associated with more lung disease pathogenesis, immune imbalance of Th17/Treg cells in patients with chronic obstructive pulmonary disease, lung cancer, pulmonary sarcoidosis and asthma among the adjustment mechanism. This article describes the progress of Th17 cells, Treg cells and Th17/Treg imbalance in lung related diseases.
[Key words] T helper 17 cells; Regulatory T cells; Pulmonary disease; Research progress
輔助性T細(xì)胞17(Th17)和調(diào)節(jié)性T細(xì)胞(Treg)是CD4+T淋巴細(xì)胞中兩個(gè)新發(fā)現(xiàn)亞群,具有促炎作用的Th17細(xì)胞和具有抑制性的Treg細(xì)胞之間的不平衡作為一種新的疾病模式已經(jīng)在各種炎癥性疾病和自身免疫性疾病中得到證實(shí)[1-2]。隨著對(duì)Th17細(xì)胞、Treg細(xì)胞的深入研究,Th17/Treg與慢性阻塞性肺疾?。–OPD)、肺癌、肺結(jié)節(jié)病及哮喘等臨床常見(jiàn)肺部疾病免疫機(jī)制的相關(guān)性研究也逐漸成為熱點(diǎn)。本文就Th17/Treg細(xì)胞在幾種臨床常見(jiàn)肺部疾病免疫機(jī)制的研究現(xiàn)狀予以綜述。
1 Th17細(xì)胞
Th17細(xì)胞是一類(lèi)CD4+效應(yīng)T細(xì)胞的亞群,目前主要依據(jù)其分泌的白介素-17(IL-17)、IL-21和IL-22等促炎因子區(qū)別于其他CD4+T效應(yīng)細(xì)胞[3]。通常情況下以IL-17的分泌代表Th17細(xì)胞的狀態(tài),以IL-17界定Th17細(xì)胞功能,Th17細(xì)胞的免疫效應(yīng)作用也是通過(guò)IL-17實(shí)現(xiàn)的[4]。在上皮細(xì)胞、成纖維細(xì)胞、單核細(xì)胞、粒-巨細(xì)胞、內(nèi)皮細(xì)胞及淋巴細(xì)胞等表面高表達(dá)IL-17受體,IL-17誘使這些靶細(xì)胞分泌IL-6、IL-8、粒細(xì)胞集落刺激因子等吸引更多炎癥細(xì)胞聚集,發(fā)揮對(duì)抗胞外細(xì)菌感染及促炎作用,從而讓機(jī)體恢復(fù)至健康狀態(tài)[5]。Th17細(xì)胞胞內(nèi)還表達(dá)特征性的轉(zhuǎn)錄因子維甲酸相關(guān)孤兒受體-γt(RORγt)。機(jī)體遭遇病原體或抗原物質(zhì)時(shí),環(huán)繞氣道的“哨兵”樹(shù)突狀細(xì)胞(DCs)及巨噬細(xì)胞識(shí)別、遞呈了抗原信息,啟動(dòng)初始T淋巴細(xì)胞介導(dǎo)的免疫應(yīng)答,其轉(zhuǎn)錄因子RORγt隨之增加并驅(qū)使T細(xì)胞表達(dá)IL-23受體,通過(guò)IL-23信號(hào)通路活化轉(zhuǎn)錄活化因子3,促進(jìn)Th17細(xì)胞的擴(kuò)增及分泌炎性細(xì)胞因子。IL-17細(xì)胞可以在抗原遞呈環(huán)節(jié)上調(diào)一些關(guān)鍵的共刺激分子,如主要組織相容性復(fù)合物體,促使樹(shù)突狀細(xì)胞抗原遞呈功能增強(qiáng)[6]。IL-17作為重要的促炎細(xì)胞因子可協(xié)同促進(jìn)一氧化氮的合成及前列腺素E2(PGE2)的表達(dá),而后兩者具有強(qiáng)烈的致炎作用[7]。IL-17與γ干擾素(IFN-γ)協(xié)同作用下,通過(guò)增加IL-8、單核細(xì)胞趨化蛋白-1的表達(dá)以誘導(dǎo)中性粒細(xì)胞活化。IL-17促進(jìn)上皮細(xì)胞釋放各種CXCL系列趨化因子、CC類(lèi)趨化因子等,使炎性反應(yīng)進(jìn)一步放大[7]。IL-6、轉(zhuǎn)化生長(zhǎng)因子β(TGF-β)是Th17細(xì)胞最主要的調(diào)控因子。去除TGF-β基因或者抑制IL-6,可使得Th17細(xì)胞分化減少,產(chǎn)生IL-17的能力下降[8]。IL-22、IL-23、IFN-γ等在Th17細(xì)胞的合成分化中起到正反饋及持續(xù)刺激的作用。IL-12、IFN-γ、SOCS3、IL-4為T(mén)h17細(xì)胞的負(fù)向調(diào)控因子,可以在抑制Th17細(xì)胞分化中發(fā)揮作用。
2 Treg細(xì)胞
Treg細(xì)胞可以通過(guò)直接接觸、殺傷免疫效應(yīng)細(xì)胞方式或間接誘導(dǎo)細(xì)胞凋亡、抑制分化等方法抑制免疫效應(yīng)細(xì)胞發(fā)揮非特異免疫作用。大多成熟Treg細(xì)胞特征性表達(dá)CD25、IL-2及叉頭狀轉(zhuǎn)錄因子p3特異性轉(zhuǎn)錄因子(Foxp3),屬于職業(yè)抑制性T淋巴細(xì)胞。Treg細(xì)胞細(xì)胞分泌多種抑制性細(xì)胞因子如TGF-β、IL-10等,發(fā)揮抑制效應(yīng)T細(xì)胞活化和增殖作用[9]。IL-10是抑制功能強(qiáng)大的細(xì)胞因子,可以與TGF-β共同誘導(dǎo)Treg不斷分化。Treg細(xì)胞表面物質(zhì)如TGF-β、CD39、FGL2等可以與抗原遞呈DCs細(xì)胞表面受體結(jié)合,使得DCs細(xì)胞成熟受到抑制,在抗原遞呈過(guò)程發(fā)揮免疫抑制作用。Treg細(xì)胞可以表達(dá)大量半乳凝素-1,促使其產(chǎn)生炎性因子受阻,使T細(xì)胞周期阻滯或凋亡[10]。Treg細(xì)胞表面多種受體如CD25、CD122等可以競(jìng)爭(zhēng)性結(jié)合及消耗IL-2。Treg細(xì)胞釋放的顆粒酶B或穿孔素可以直接殺傷自然殺傷細(xì)胞(NK)和CD8+T細(xì)胞[11]。而Foxp3作為T(mén)reg細(xì)胞最具有特異性轉(zhuǎn)錄因子,除了標(biāo)志性存在外,在免疫抑制過(guò)程中也具有重要作用。Foxp3通過(guò)阻斷多種炎性因子在核轉(zhuǎn)錄因子kappa B(NF-κB)途徑上轉(zhuǎn)錄,從而阻斷炎性因子基因表達(dá)[12];Foxp3還可以通過(guò)與干擾轉(zhuǎn)錄活化T細(xì)胞核因子在特定區(qū)域的活化,使IL-2、IL-4、IFN-γ等細(xì)胞因子合成受抑制。endprint
3 Th17/Treg細(xì)胞平衡
Th17細(xì)胞與Treg細(xì)胞關(guān)系密切而復(fù)雜,起源同一類(lèi)初始CD4+T細(xì)胞,在細(xì)胞分化過(guò)程中相互制衡,功能上相互拮抗,在一定條件下還可以相互轉(zhuǎn)化。有研究發(fā)現(xiàn)給予TGF-β單獨(dú)作用下,初始T細(xì)胞可以向Treg細(xì)胞方向分化,TGF-β誘導(dǎo)表達(dá)Foxp3可拮抗轉(zhuǎn)錄因子RORγt朝向Th17細(xì)胞生成[13]。在TGF-β、IL-6共同作用下,主要向Th17細(xì)胞分化,由于有IL-6的存在,Treg細(xì)胞分化會(huì)受到一定抑制。有研究報(bào)道大量IL-6、IL-21還可以使得已經(jīng)分化的Treg細(xì)胞向Th17細(xì)胞轉(zhuǎn)化[14-15]。
4 Th17/Treg細(xì)胞與肺部疾病
4.1 Th17/Treg細(xì)胞與COPD
COPD是一種以持續(xù)性呼吸道癥狀和氣流受限為主要特征的可預(yù)防可治療的常見(jiàn)慢性肺部疾病,氣流受限是由有毒顆?;驓怏w導(dǎo)致,并伴有氣道和(或)肺泡異常炎性反應(yīng)的增加[16]。吸煙是主要的危險(xiǎn)因素。國(guó)內(nèi)外研究發(fā)現(xiàn)在吸煙者和COPD患者的肺組織中及誘導(dǎo)痰中IL-17均是增多的,COPD患者外周血中Th17細(xì)胞明顯高于健康對(duì)照組[17-19]。Th17細(xì)胞及相關(guān)細(xì)胞因子的增加程度與肺功能呈負(fù)相關(guān),隨著急性加重期的嚴(yán)重程度呈遞增趨勢(shì),病情趨向于平穩(wěn)進(jìn)入穩(wěn)定期時(shí)Th17細(xì)胞在肺內(nèi)及外周血的表達(dá)較急性加重期有所減少,但仍高于正常健康人群[20]。有研究發(fā)現(xiàn)IL-17亦參與了COPD的氣道重塑及肺血管重構(gòu)的病理過(guò)程[21]。Treg細(xì)胞在不同區(qū)域分布及動(dòng)態(tài)變化爭(zhēng)議較大,國(guó)外Smyth等[22]研究發(fā)現(xiàn)COPD組及吸煙人群的支氣管肺泡灌洗液(BALF)中CD4+CD25+Treg細(xì)胞數(shù)量較正常人明顯減少。本課題組前期實(shí)驗(yàn)通過(guò)流式細(xì)胞技術(shù)檢測(cè)COPD小鼠肺內(nèi)、BALF及外周血中Treg細(xì)胞較野生型小鼠減少[23]。提示Treg細(xì)胞的數(shù)目及功能在COPD疾病過(guò)程中均存在不足。但我國(guó)章穎妹等[24]研究發(fā)現(xiàn)COPD患者肺內(nèi)Treg細(xì)胞浸潤(rùn)表達(dá)較對(duì)照組減少,外周血Treg細(xì)胞比例升高。研究通過(guò)短期煙熏過(guò)程后Foxp3含量可表達(dá)增多,長(zhǎng)期慢性煙熏后減少[25],也有研究者發(fā)現(xiàn)香煙煙霧暴露后,大氣道的Treg細(xì)胞表達(dá)增多,小氣道及肺泡減少[26]。這些增加的Treg細(xì)胞被認(rèn)為可能已經(jīng)失去調(diào)節(jié)功能[27]。Li等[28]通過(guò)流式細(xì)胞技術(shù)檢測(cè)到COPD患者的外周循環(huán)中存在Th17/Treg失衡。COPD患者體內(nèi)的Th17/Treg失衡偏向Th17細(xì)胞,Th17/Treg細(xì)胞比值從對(duì)照組、吸煙無(wú)COPD組和吸煙COPD組呈遞增性趨勢(shì),與肺功能的惡化有相關(guān)性[29-30]。所以,Th17/Treg失衡導(dǎo)致免疫紊亂可能是引起COPD發(fā)生發(fā)展的重要原因。
4.2 Th17/Treg細(xì)胞與肺癌
大多數(shù)肺癌起源于支氣管黏膜上皮,研究發(fā)現(xiàn),聚集環(huán)繞在腫瘤周?chē)腡reg細(xì)胞增多,通過(guò)多種途徑抑制DCs細(xì)胞的識(shí)別及遞呈,同時(shí)抑制效應(yīng)T淋巴細(xì)胞的活化,Treg細(xì)胞產(chǎn)生的抑制因子如TGF-β和PGE2可對(duì)抗癌細(xì)胞凋亡,Treg細(xì)胞可以分泌穿孔素和顆粒酶可直接殺傷CD8+T細(xì)胞及NK細(xì)胞,介導(dǎo)免疫逃逸使巢內(nèi)癌細(xì)胞得以保護(hù)呈迅速生長(zhǎng)。外周血的Treg細(xì)胞和Foxp3均有上調(diào),拮抗Th17細(xì)胞分化,利于肺內(nèi)腫瘤生長(zhǎng)[31]。Treg細(xì)胞被認(rèn)為是肺癌免疫調(diào)節(jié)機(jī)制的核心。Th17細(xì)胞作為自身對(duì)腫瘤細(xì)胞有殺傷功能的一群效應(yīng)T細(xì)胞,在腫瘤局部?jī)?nèi)部及周邊均有上調(diào),分泌IL-17F、IL-21、IL-22可以對(duì)抗腫瘤血管形成,也有研究發(fā)現(xiàn),IL-17可通過(guò)招募部分骨髓細(xì)胞和促進(jìn)炎癥加速癌細(xì)胞局部的發(fā)展及遠(yuǎn)處轉(zhuǎn)移,并且還可以增強(qiáng)血管內(nèi)皮生長(zhǎng)因子的產(chǎn)生從而為腫瘤新生血管提供條件[32]。Treg/Th17細(xì)胞比值的變化與非小細(xì)胞性肺癌的預(yù)后有相關(guān)性,Treg細(xì)胞顯著高表達(dá)于肺癌進(jìn)展期及有肺外轉(zhuǎn)移灶階段,導(dǎo)致Treg/Th17細(xì)胞平衡偏向Treg細(xì)胞,同時(shí)化療后外周血中Treg/Th17細(xì)胞以及較化療前均明顯降低,提示Th17細(xì)胞與Treg細(xì)胞的動(dòng)態(tài)平衡與肺癌的臨床分期、病理分型、淋巴結(jié)轉(zhuǎn)移和分化程度密切相關(guān)[33-34]。
4.3 Th17/Treg細(xì)胞與肺結(jié)節(jié)病
結(jié)節(jié)病是一種病因未明、多器官受累的非干酪樣壞死性肉芽腫性疾病,90%累及胸內(nèi)淋巴結(jié)及肺臟。結(jié)節(jié)病患者在處于活動(dòng)期時(shí)外周血及BALF中Th17細(xì)胞比例顯著升高,胸內(nèi)淋巴結(jié)及肺組織標(biāo)本免疫組化顯示IL-17、IL-23圍繞肉芽腫浸潤(rùn)高表達(dá)以及皮下IL-22陽(yáng)性細(xì)胞比例增加。在緩解期或自限性病程中有下降趨勢(shì),在復(fù)發(fā)的結(jié)節(jié)病中這一趨勢(shì)再次升高。Kaiser等[35]及黃慧[36]報(bào)道:BALF中Th17細(xì)胞百分比及相關(guān)細(xì)胞因子IL-17、IL-23均高于外周血。Th1/Th17細(xì)胞的共表達(dá)轉(zhuǎn)錄因子T-bet及RORγt存在BALF的T細(xì)胞里,而不是外周血中,表明Th17細(xì)胞及相關(guān)細(xì)胞因子主要是通過(guò)局部免疫增強(qiáng)參與肺結(jié)節(jié)病的免疫紊亂過(guò)程[35]。目前國(guó)內(nèi)外對(duì)Treg細(xì)胞在肺結(jié)節(jié)病的數(shù)量及分布存在一些分歧,Idali等[37]及黃慧[36]發(fā)現(xiàn),結(jié)節(jié)病患者的Treg細(xì)胞不但存在數(shù)量的減少、相關(guān)抑制作用的細(xì)胞因子表達(dá)水平下降,而且BALF中的CD4+T細(xì)胞胞內(nèi)Foxp3信使核糖核酸表達(dá)亦是下降的,從而導(dǎo)致Treg細(xì)胞在結(jié)節(jié)病中免疫抑制功能的減退。但Miyara等[38]研究認(rèn)為結(jié)節(jié)病患者體內(nèi)Treg細(xì)胞的比例是增加的?;顒?dòng)期外周血CD4+CD25+Treg細(xì)胞比例高于非活動(dòng)期和健康人群。肺內(nèi)肉芽腫組織和淋巴結(jié)內(nèi)Treg細(xì)胞表達(dá)升高[39]。在結(jié)節(jié)病損害處的炎性反應(yīng)存在不受控制現(xiàn)象。Treg細(xì)胞不能完全抑制肉芽腫內(nèi)IFN-γ、腫瘤壞死因子α(TNF-α)的分泌,認(rèn)為T(mén)reg細(xì)胞在結(jié)節(jié)病的嚴(yán)重組織受損過(guò)程中并沒(méi)有起到有效的保護(hù)作用,即使Treg細(xì)胞數(shù)量正?;蛟黾?,仍有局部Treg細(xì)胞功能“失能”[40]。由于外周血Treg細(xì)胞具有正常免疫抑制功能,若相對(duì)數(shù)量增加又會(huì)導(dǎo)致機(jī)體免疫力低下。結(jié)節(jié)病患者容易出現(xiàn)機(jī)會(huì)性感染、合并腫瘤以及大多數(shù)患者對(duì)結(jié)核分枝桿菌的PPD試驗(yàn)出現(xiàn)無(wú)反應(yīng),也許與外周血Treg細(xì)胞的抑制功能存在相關(guān)性。有研究發(fā)現(xiàn)Lofgren綜合征的患者(具有自限性病程、良好預(yù)后的一類(lèi))肺內(nèi)Th17、Th1混合細(xì)胞及相關(guān)轉(zhuǎn)錄因子表達(dá)水平均比有慢性進(jìn)展病程的患者顯著升高,目前Th17/Treg平衡是否參與結(jié)節(jié)病發(fā)生、發(fā)展及預(yù)后仍需要進(jìn)一步證實(shí)。endprint
4.4 Th17/Treg細(xì)胞與支氣管哮喘
近幾年研究發(fā)現(xiàn)哮喘患者的痰中及外周血均見(jiàn)Th17細(xì)胞及相關(guān)炎性細(xì)胞因子增加,與氣道高反應(yīng)呈正相關(guān)[41-42]。動(dòng)物實(shí)驗(yàn)中,向小鼠體內(nèi)注入致敏Th17細(xì)胞后可促使中性粒細(xì)胞和淋巴細(xì)胞向肺組織浸潤(rùn),IL-17、IL-22敲除的小鼠其致敏發(fā)作后的氣道炎癥有所減輕,氣道高反應(yīng)性均低于野生型小鼠[43]。提示Th17細(xì)胞可促進(jìn)哮喘急性發(fā)作。Zijlstra等[43]研究發(fā)現(xiàn)IL-17A可通過(guò)活化磷脂酰肌醇3激酶及組蛋白脫乙酰酶2誘導(dǎo)氣道上皮對(duì)糖皮質(zhì)激素治療不敏感[44]。在哮喘不同階段存在Treg細(xì)胞功能及數(shù)目的改變。Qin等[45]的研究發(fā)現(xiàn)過(guò)敏性哮喘穩(wěn)定期患者和正常健康組外周血Treg細(xì)胞數(shù)目并無(wú)明顯差異,而哮喘加重期確有明顯升高,并在其功能上未見(jiàn)明顯受損,在重度哮喘的患者的BALF中Treg細(xì)胞數(shù)目增多。在哮喘患者的外周血及誘導(dǎo)痰中存在Th17/Treg細(xì)胞失衡,哮喘模型小鼠體內(nèi)Th17/Treg細(xì)胞比值升高[42-46]。Th17/Treg細(xì)胞平衡在哮喘的發(fā)病過(guò)程中發(fā)揮重要作用。
綜上所述,隨著基礎(chǔ)免疫學(xué)的認(rèn)識(shí)不斷深入,Th17細(xì)胞、Treg細(xì)胞及Th17/Treg細(xì)胞失衡可能是多種肺部疾病免疫調(diào)控系統(tǒng)的核心機(jī)制之一。不同組織、不同微環(huán)境下其具體機(jī)制仍存在諸多差異,雖然Th17/Treg細(xì)胞免疫機(jī)制的失調(diào)可能是導(dǎo)致疾病的發(fā)生發(fā)展的重要原因,但關(guān)鍵環(huán)節(jié)仍未明確。針對(duì)Th17/Treg細(xì)胞在多種肺部發(fā)病機(jī)制中的作用,仍需要大量研究進(jìn)一步闡明。
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(收稿日期:2017-09-05 本文編輯:李岳澤)endprint