結(jié)核病細(xì)胞免疫特征研究進(jìn)展①

李 麗

(武漢市肺科醫(yī)院(武漢市結(jié)核病防治所)中心實(shí)驗(yàn)室,武漢430030)

結(jié)核病細(xì)胞免疫特征研究進(jìn)展①

李 麗

(武漢市肺科醫(yī)院(武漢市結(jié)核病防治所)中心實(shí)驗(yàn)室,武漢430030)

結(jié)核病是典型的胞內(nèi)寄生菌誘導(dǎo)的感染性疾病，其感染、發(fā)病及預(yù)后等都與機(jī)體免疫功能息息相關(guān)。結(jié)核分枝桿菌誘導(dǎo)的免疫應(yīng)答機(jī)制及參與因素十分復(fù)雜，目前認(rèn)為T細(xì)胞介導(dǎo)的細(xì)胞免疫應(yīng)答在其感染及發(fā)病過程中發(fā)揮關(guān)鍵作用。而T細(xì)胞無論是從表型、功能還是體內(nèi)定位來講，其異質(zhì)性特征都非常顯著。結(jié)核分枝桿菌感染機(jī)體后，多種T細(xì)胞亞群被激活，參與結(jié)核菌誘導(dǎo)的免疫應(yīng)答及免疫病理過程。本文綜述近年來結(jié)核桿菌感染或結(jié)核病發(fā)病過程中的主要T細(xì)胞亞群及其特征和功能，為深入理解結(jié)核桿菌誘導(dǎo)的免疫應(yīng)答提供參考。

1 結(jié)核桿菌特異性效應(yīng)性細(xì)胞免疫應(yīng)答

1.1特異性細(xì)胞免疫應(yīng)答的啟動(dòng) 結(jié)核桿菌主要感染肺泡巨噬細(xì)胞，結(jié)核桿菌與巨噬細(xì)胞表面特異性受體結(jié)合，攝取后形成吞噬體，被加工后，分別和HLA-Ⅰ類和Ⅱ類分子結(jié)合，提呈給CD8+T和CD4+T細(xì)胞。除了直接提呈抗原，也可發(fā)生間接抗原提呈或交叉提呈，其中一個(gè)主要方式是，死亡細(xì)胞釋放的結(jié)核抗原被樹突狀細(xì)胞(DCs)攝取，然后和HLA一類分子結(jié)合從而發(fā)生交叉提呈并激活CD8+T細(xì)胞[1]。

1.2結(jié)核抗原特異性T細(xì)胞發(fā)揮關(guān)鍵保護(hù)作用 抗原特異性T細(xì)胞活化、擴(kuò)增并遷移到肺部，通過活化巨噬細(xì)胞和細(xì)胞毒性T細(xì)胞靶向殺傷結(jié)核桿菌感染的巨噬細(xì)胞，發(fā)揮有效抗結(jié)核菌免疫應(yīng)答。雖然T細(xì)胞在控制結(jié)核方面發(fā)揮關(guān)鍵作用，但具體哪個(gè)T細(xì)胞亞群或何種T細(xì)胞功能發(fā)揮關(guān)鍵保護(hù)作用還不完全清楚。有關(guān)TB-HIV共感染的流行病學(xué)研究表明，當(dāng)HIV感染導(dǎo)致CD4+T細(xì)胞數(shù)量下降時(shí)，活動(dòng)性肺結(jié)核發(fā)生率顯著上升[2]。在HIV感染早期，結(jié)核菌誘導(dǎo)結(jié)核特異性T細(xì)胞CCR5表達(dá)上升，由于CCR5是HIV結(jié)合T細(xì)胞的受體，從而增加了結(jié)核特異性T細(xì)胞被HIV感染的可能性，導(dǎo)致結(jié)核特異性T細(xì)胞下降[2]。此外，結(jié)核特異性T細(xì)胞單細(xì)胞水平表達(dá)高水平IL-2，促進(jìn)T細(xì)胞增殖，也增加其被HIV感染的可能性[3]。HIV感染CD4+T細(xì)胞，其中也包括結(jié)核特異性CD4+T細(xì)胞，導(dǎo)致這些輔助性T細(xì)胞數(shù)量顯著下降從而抗結(jié)核作用下降，表明CD4+T細(xì)胞是控制結(jié)核所必需的。

1.3結(jié)核特異性Th1細(xì)胞的作用 根據(jù)其功能的不同，CD4+T細(xì)胞又可分為不同的細(xì)胞亞群，其中Th1細(xì)胞可產(chǎn)生多種關(guān)鍵的細(xì)胞因子，包括IFN-γ、IL-2和TNF-α。TNF-α對于結(jié)核肉芽腫的形成和維持非常重要，是抗結(jié)核免疫的關(guān)鍵成分。在類風(fēng)濕性關(guān)節(jié)炎(RA)或炎癥性腸炎患者，使用抗TNF抗體后結(jié)核復(fù)發(fā)危險(xiǎn)性增加[4,5]。IFN-γ是另一種抗結(jié)核關(guān)鍵細(xì)胞因子，常被作為診斷性生物標(biāo)記。IL-12/IL-23-IFN-γ細(xì)胞因子信號途徑缺陷者對于非結(jié)核分枝桿菌及結(jié)核桿菌易感性增加[6]，表明IFN-γ在機(jī)體抗結(jié)核中的重要作用。最近在小鼠模型中發(fā)現(xiàn)某種CD4+Th1細(xì)胞可通過不依賴IFN-γ和TNF-α的方式控制結(jié)核感染[7]，人體是否存在這種細(xì)胞還不明確。

由于在抗結(jié)核免疫應(yīng)答中的重要作用，利用結(jié)核抗原刺激來誘導(dǎo)IFN-γ已被廣泛應(yīng)用于商業(yè)化免疫診斷測試如Quantiferon-TB Gold和T-SPOT TB。而且，在臨床疫苗試驗(yàn)中，IFN-γ也經(jīng)常被作為疫苗誘導(dǎo)應(yīng)答的指示性細(xì)胞因子。然而，也有研究表明，可產(chǎn)生IFN-γ的CD4+T和CD8+T細(xì)胞頻率并不與抗結(jié)核保護(hù)性相關(guān)[8-12]。在南非，利用卡介苗(BCG)對嬰兒進(jìn)行初免然后利用MVA85A加強(qiáng)免疫可顯著增強(qiáng)產(chǎn)生IFN-γ的T細(xì)胞頻率。但在最近的大規(guī)模Ⅱb臨床試驗(yàn)中，并未發(fā)現(xiàn)其有更好的保護(hù)效果[8,9]。T細(xì)胞來源的IFN-γ需要維生素D來刺激巨噬細(xì)胞發(fā)揮自噬作用，吞噬體成熟，以發(fā)揮抗菌活性。因此，無論固有免疫或是適應(yīng)性免疫均需維生素D來促進(jìn)巨噬細(xì)胞依賴性抗菌活性。維生素D受體及循環(huán)中維生素D的水平對于有效控制結(jié)核來說很關(guān)鍵。

1.4結(jié)核特異性多功能性Th1 細(xì)胞的作用 抗結(jié)核保護(hù)性免疫可能與多功能的可同時(shí)分泌IFN-γ、TNF-α和IL-2的細(xì)胞相關(guān)。在動(dòng)物實(shí)驗(yàn)中，這群細(xì)胞與疫苗誘導(dǎo)保護(hù)性作用相關(guān)[10,11,13-18]。然而，雖然在動(dòng)物和人體試驗(yàn)中都發(fā)現(xiàn)疫苗免疫后可誘導(dǎo)多功能性CD4+T細(xì)胞[12-18]，但其在活動(dòng)性肺結(jié)核患者外周血中也大量存在[19,20]，這群細(xì)胞并不與保護(hù)作用相關(guān)[12]。在TB-HIV共感染個(gè)體中多功能T細(xì)胞的作用也存在爭議，有研究報(bào)道這些患者在診斷為結(jié)核時(shí)存在多功能性CD4+T細(xì)胞[21]，有的則是在接受抗逆轉(zhuǎn)錄病毒治療后發(fā)現(xiàn)多功能性CD4+T細(xì)胞[22]。因此，多功能CD4+T細(xì)胞可能只是機(jī)體免疫系統(tǒng)中控制結(jié)核感染的保護(hù)性應(yīng)答力量的一部分，而并不是一個(gè)有效的可用于衡量機(jī)體抗結(jié)核保護(hù)作用的指標(biāo)。相反，Th1和Th17應(yīng)答的強(qiáng)度、多功能T細(xì)胞的強(qiáng)度被認(rèn)為與結(jié)核活動(dòng)性相關(guān)，可能反映細(xì)菌水平而非保護(hù)性免疫水平[20,23]。

1.5結(jié)核特異性CD8+T細(xì)胞的作用 通過HLA-Ⅰ類分子四聚體和生物信息學(xué)技術(shù)，可詳盡研究抗結(jié)核CD8+T細(xì)胞表位、應(yīng)答及多功能細(xì)胞因子特征。大多CD8+T細(xì)胞識(shí)別HLA-Ⅰa類分子提呈抗原，這些細(xì)胞可產(chǎn)生多種細(xì)胞因子[24]。在結(jié)核患者，治療過程中產(chǎn)生IFN-γ的結(jié)核特異性CD8+T細(xì)胞水平迅速下降[25]，而也有研究表明HLA-Ⅰa四聚體陽性CD8+T 細(xì)胞水平隨著抗結(jié)核治療而逐漸上升[26]，導(dǎo)致這種矛盾的原因并不清楚。但有可能是結(jié)核特異性CD8+T細(xì)胞并不完全具有功能性或者抗結(jié)核化療后功能并不能完全恢復(fù)[27]。動(dòng)物實(shí)驗(yàn)表明，CD8+T細(xì)胞應(yīng)答強(qiáng)度與細(xì)菌水平相關(guān)[28-30]。CD8+T細(xì)胞分泌的IFN-γ和穿孔素對于發(fā)揮抗結(jié)核保護(hù)作用來說是必需的[28-30]。CD4+T細(xì)胞可促進(jìn)細(xì)胞毒性CD8+T細(xì)胞的活化，也可激活巨噬細(xì)胞，其活化后提呈抗原給T細(xì)胞的功能增加，促進(jìn)肉芽腫形成及殺菌機(jī)制激活以殺傷結(jié)核菌。

2 結(jié)核誘導(dǎo)的調(diào)節(jié)性T細(xì)胞和Th17細(xì)胞

除了激活效應(yīng)性免疫應(yīng)答，結(jié)核菌還激活調(diào)節(jié)性T細(xì)胞(Treg)，抑制炎癥、限制組織損傷，去除這群細(xì)胞可增強(qiáng)抗結(jié)核效應(yīng)免疫。Treg和效應(yīng)T細(xì)胞之間的平衡對疾病的發(fā)展和結(jié)局非常重要，過強(qiáng)的效應(yīng)性應(yīng)答會(huì)導(dǎo)致強(qiáng)烈炎癥反應(yīng)、組織損傷；而過強(qiáng)的Treg應(yīng)答則會(huì)下調(diào)效應(yīng)免疫導(dǎo)致結(jié)核菌免疫逃逸、大量復(fù)制。

Th17可分泌IL-17A/F和IL-22，有強(qiáng)促炎作用，在黏膜免疫中發(fā)揮重要作用。結(jié)核患者外周血可見Th17細(xì)胞，為長壽命記憶性細(xì)胞，而在發(fā)病局部較難檢測到IL-17，卻可發(fā)現(xiàn)大量IL-22[31]。有研究表明IL-17在抗高毒性結(jié)核分枝桿菌中發(fā)揮重要保護(hù)作用[32]。而且，Th17的強(qiáng)度對于感染結(jié)局非常重要，當(dāng)小鼠反復(fù)暴露于結(jié)核分枝桿菌和BCG，產(chǎn)生大量IL-23，誘導(dǎo)Th17應(yīng)答，其中IL-17/巨噬細(xì)胞炎性蛋白2(MIP-2)激活中性粒細(xì)胞，誘導(dǎo)肺臟病理改變，這種反應(yīng)并非保護(hù)性免疫[33]。因此，Th1和Th17之間的平衡對于保護(hù)性或是病理性免疫來說至關(guān)重要。類似，在BCG誘導(dǎo)靈長類動(dòng)物保護(hù)性模型中，Th1和Th17之間的平衡對于控制結(jié)核分枝桿菌非常重要，與保護(hù)性相關(guān)[34]。

3 結(jié)核誘導(dǎo)的非經(jīng)典T細(xì)胞亞群

3.1結(jié)核桿菌誘導(dǎo)的黏膜相關(guān)恒定T細(xì)胞(MAIT細(xì)胞) 其他非經(jīng)典限制性T細(xì)胞亞群，包括非多態(tài)性Ⅰb分子MHC相關(guān)蛋白1(MR1)限制性T細(xì)胞，也稱作MAIT，表達(dá)半保守Vα7.2T細(xì)胞受體[35]，與iNKT細(xì)胞類似。人體MAIT主要存在于CD4-CD8-雙陰性細(xì)胞或CD8+T細(xì)胞[35-37]，其在胸腺中發(fā)育和在外周的活化受MR1限制[38]。除了分泌TNF-α和IFN-γ外，MAIT還分泌IL-17A和IL-22，發(fā)揮抗菌活性。MR1提呈維生素代謝物，大多為細(xì)菌和酵母所特有的VitB產(chǎn)物[39]，MAIT可能利用這些代謝物來感知感染細(xì)胞。MAIT可由結(jié)核感染肺上皮細(xì)胞所激活[40，41]。相比野生型小鼠，MAIT缺陷小鼠感染卡介苗后早期肺部結(jié)核菌數(shù)量更高，表明其在抗結(jié)核早期固有免疫中發(fā)揮重要作用[42]。通過表型CD161highCD8+分析MAIT，提示這些細(xì)胞在HIV感染患者中下降，這與其黏膜免疫抵抗力下降相關(guān)，導(dǎo)致其對結(jié)核易感性增加[43]。此外，也有研究發(fā)現(xiàn)，活動(dòng)性結(jié)核患者，由于MAIT遷移到疾病局部[35,44]，從而導(dǎo)致外周MAIT細(xì)胞頻率下降。最新研究發(fā)現(xiàn)，結(jié)核患者和非結(jié)核分枝桿菌(NTM)感染患者M(jìn)AIT數(shù)量和功能均存在缺陷，MAIT表達(dá)PD-1水平上升，導(dǎo)致IFN-γ分泌功能缺陷，抗結(jié)核保護(hù)作用下降[45]。阻斷PD-1信號導(dǎo)致IFN-γ產(chǎn)生顯著增加，因此，這可能是結(jié)核免疫治療的重要靶點(diǎn)[46]。

除了經(jīng)典HLA-Ⅰa類分子，結(jié)核抗原也可通過非經(jīng)典HLA-Ⅰb分子，如CD1、HLA-E和MR1提呈給CD8+T細(xì)胞。識(shí)別HLA-E分子提呈的結(jié)核抗原肽的CD8+T細(xì)胞具有殺傷或調(diào)節(jié)功能。HIV-nef不能結(jié)合HLA-E胞內(nèi)部分，因此HIV感染對HLA-E提呈抗原功能影響并不十分顯著，而HLA-Ⅰa提呈抗原能力則受到較大影響[47]。此外，結(jié)核分枝桿菌脂質(zhì)抗原經(jīng)CD1分子提呈，被CD4+T細(xì)胞識(shí)別，誘導(dǎo)細(xì)胞因子和細(xì)胞毒性殺傷感染靶細(xì)胞[48]。

4 結(jié)語

隨著結(jié)核合并其他疾病(如HIV/AIDS、糖尿病)、耐藥結(jié)核甚至耐多藥結(jié)核的出現(xiàn)，有關(guān)結(jié)核免疫功能的研究面臨越來越復(fù)雜的形勢，這也使得我們對于結(jié)核誘導(dǎo)免疫應(yīng)答的多面性、階段性及異質(zhì)性有更清晰的認(rèn)識(shí)。有關(guān)結(jié)核免疫功能研究不應(yīng)是孤立的，應(yīng)綜合代謝組學(xué)、基因組學(xué)、蛋白質(zhì)組學(xué)、表觀遺傳學(xué)等不同學(xué)科、多種技術(shù)手段加以綜合分析以獲得更全面、客觀的信息。深入理解結(jié)核桿菌誘導(dǎo)的免疫功能特征，對于結(jié)核的早期診斷、有效免疫干預(yù)措施的制訂、預(yù)后判斷及新型結(jié)核疫苗的設(shè)計(jì)都十分重要。

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[收稿2016-09-12 修回2016-12-21]

(編輯 倪 鵬)

10.3969/j.issn.1000-484X.2017.06.032

①本文受湖北省自然科學(xué)基金項(xiàng)目(2015CFB255)、武漢市中青年醫(yī)學(xué)骨干人才培養(yǎng)工程(武衛(wèi)生計(jì)生通[2015]9號)和武漢市黃鶴英才(醫(yī)療衛(wèi)生)計(jì)劃(武人才辦2016[1]號)資助。

李 麗(1980年-)，女，博士，副主任技師，主要從事結(jié)核病免疫學(xué)方面的研究，E-mail:ly_li@aliyun.com。

R392

A

1000-484X(2017)06-0955-04