葉麗萍 胡靜濤 王春鳳

(吉林農(nóng)業(yè)大學(xué)動(dòng)物科學(xué)技術(shù)學(xué)院，長(zhǎng)春130118)

樹突狀細(xì)胞與輪狀病毒相互作用機(jī)制研究進(jìn)展①

葉麗萍 胡靜濤 王春鳳

(吉林農(nóng)業(yè)大學(xué)動(dòng)物科學(xué)技術(shù)學(xué)院，長(zhǎng)春130118)

輪狀病毒(Rotavirus，RV)屬于呼腸孤病毒科輪狀病毒屬成員，是引起嬰幼兒和其他幼齡動(dòng)物腹瀉的主要病原之一，全世界每年約有400 000名兒童因感染此病毒而死亡[1]。RV感染已成為全球性的健康問題，各國(guó)研究人員對(duì)其感染的特點(diǎn)、免疫反應(yīng)及疫苗開發(fā)做了大量的研究[2-4]。RV感染機(jī)體首先入侵腸道，以腸道黏膜免疫為主誘導(dǎo)機(jī)體免疫應(yīng)答[5,6]，但其免疫機(jī)理目前尚未完全清楚，研究RV感染的黏膜免疫機(jī)制將對(duì)疫苗的開發(fā)和疾病的防治至關(guān)重要。黏膜免疫是連接固有免疫和獲得性免疫的橋梁，其中樹突狀細(xì)胞(Dendritic cells,DCs)作為重要的抗原遞呈細(xì)胞(Antigen presentation cells，APC)起著銜接固有免疫和獲得性免疫的關(guān)鍵免疫分子作用[7,8]。本文就RV感染對(duì)DCs的影響及相互作用機(jī)制的研究做一綜述。

1 與RV感染相關(guān)的DCs分類

RV感染機(jī)體主要入侵腸道上皮細(xì)胞而導(dǎo)致腸絨毛損傷，腸道DCs的表型各不相同，但多以CD11chighMHCⅡhighDCs為主[9]。根據(jù)胃腸道淋巴結(jié)、派氏集合淋巴結(jié)(Peyer′s patch，PP)等是否表達(dá)CD11b和CD8α，將DCs分為CD11c+CD11b+CD8α-、CD11c+CD11b-CD8α+、CD11c+CD11b-CD8α-及CD11c+CD11cintCD8α+B220+四個(gè)亞群[10]。腸道中CD103+DCs還可分為CD103+CD11b+和CD103+CD11b-兩個(gè)亞群，CD103+CD11b+DCs具有分泌淋巴細(xì)胞并促進(jìn)T細(xì)胞產(chǎn)生免疫應(yīng)答作用[9]；而小腸黏膜固有層(Lamina propria，LP)中的CD103+DCs主要是CD11chiCD11bhiDCs亞群，能特異表達(dá)TLR5和誘導(dǎo)固有B細(xì)胞分化IgA+類漿細(xì)胞[11]。除此，Henri等[12]發(fā)現(xiàn)小鼠腸系膜淋巴結(jié)(Mesenteric lymph nodes，MLN)中存在CD11b+CD4+和CD4-CD8-DEC-205intDCs亞群。

2 RV感染與DCs相互作用機(jī)制

DCs對(duì)腸黏膜部入侵的病原體起到免疫識(shí)別、免疫應(yīng)答和免疫調(diào)節(jié)作用，其數(shù)量和成熟狀態(tài)直接影響腸道免疫應(yīng)答能力。當(dāng)腸道發(fā)生感染，源于多能造血干細(xì)胞的未成熟DCs(Immature DCs，IDCs)通過外周血液循環(huán)進(jìn)入淋巴組織，攝取抗原發(fā)育為成熟DCs(Mature DCs，MDCs)并促進(jìn)T、B淋巴細(xì)胞產(chǎn)生相應(yīng)的免疫應(yīng)答。RV與DCs相互作用是誘導(dǎo)還是抑制DCs成熟，DCs如何在抗RV感染中起著銜接固有免疫和獲得性免疫關(guān)鍵分子作用，學(xué)者們做了大量研究。

2.1RV感染誘導(dǎo)/抑制DCs活化成熟 正常情況下絕大多數(shù)組織和器官內(nèi)的DCs屬于IDCs，起到免疫監(jiān)視作用，低表達(dá)共刺激分子CD80、CD86、CD40和MHCⅡ。當(dāng)病原體侵入機(jī)體，DCs被活化為MDCs抗原遞呈能力增強(qiáng)，能夠有效的將處理的抗原遞呈給初始T細(xì)胞使之活化，從而啟動(dòng)免疫應(yīng)答[13,14]。DCs成熟主要表現(xiàn)為共刺激分子的表達(dá)上調(diào)，趨化因子受體和細(xì)胞因子產(chǎn)生的變化，涉及到的信號(hào)通路包括NF-κB/IκBα、PI3K/Akt、MAPK/Erk/p38和MyD88/IRFs[14,15]。作者研究表明豬輪狀病毒DN30209株能誘導(dǎo)小鼠BMDCs的成熟與活化，上調(diào)表達(dá)MHCⅡ和共刺激分子CD40、CD80、CD86，DCs的抗原遞呈能力增強(qiáng)，通過TLR3/TRIF/NF-κB信號(hào)和TLR2/MyD88/NF-κB信號(hào)通路參與免疫應(yīng)答。

RV感染促進(jìn)DCs活化成熟還是導(dǎo)致細(xì)胞凋亡仍無定論。Narvaez等[16]研究認(rèn)為RRV不誘導(dǎo)IDCs和MDCs凋亡，能誘導(dǎo)大約20%的IDCs成熟但不會(huì)改變MDCs的表型變化；互作用24 h后MDCs較IDCs表達(dá)更多的CD83和NSP4，表明RRV易感染MDCs。Istrate等[17]認(rèn)為活的牛輪狀病毒RF-81株(RFV)、RF 2/6-GFP-VLP和RF 8*2/6/7-VLP中RFV能上調(diào)共刺激分子CD86的表達(dá)，刺激骨髓樹突細(xì)胞(Bone marrow-derived dendritic cells ，BMDCs)活化成熟，而且RFV能在BMDCs中表達(dá)病毒蛋白。Rodriguez等[18]的研究發(fā)現(xiàn)，RRV感染Caco-2細(xì)胞上清液刺激IDC 與單純用RRV刺激IDC HLA-DR和CD86表達(dá)明顯增加；單純用RRV刺激IDCs可以提高CD83、HLA-DR、CD86的表達(dá)。Rosales-Martinez等[19]的研究則認(rèn)為恒河猴輪狀病毒(Rhesus monkey rotavirus，RRV)能活化新生兒臍帶血(Umbilical cord blood,UCB)DCs，上調(diào)表達(dá)CD40、CD86和MHCⅡ，流式細(xì)胞術(shù)檢測(cè)發(fā)現(xiàn)2% UCB DCs和28% PB DCs感染RRV。Mesa等[20]的研究認(rèn)為mDC和pDC與RRV作用的初期即被感染，pDC能產(chǎn)生RV特異性記憶性T細(xì)胞參與免疫反應(yīng)。

2.2RV感染的Toll樣受體信號(hào)通路 Toll樣受體(Toll-like receptors，TLRs)作為重要的病原體相關(guān)分子模式(Pathogen-associated molecular patterns， PAMP)，其信號(hào)通路在誘導(dǎo)DCs成熟及激活固有免疫應(yīng)答過程中起著重要作用[21,22]。RV感染時(shí)單核細(xì)胞表達(dá)的TLRs可通過識(shí)別dsRNA激活NF-κB和干擾素途徑，導(dǎo)致細(xì)胞因子及輔助刺激分子的釋放，調(diào)節(jié)機(jī)體非特異性免疫應(yīng)答[22]。Pott等[23]的研究認(rèn)為RV感染后TLR3的表達(dá)量明顯高于TLR2、TLR4、TLR6-9，且成年鼠Tlr3誘導(dǎo)的免疫反應(yīng)能更有效地抑制RV復(fù)制。Rosales-Martinez等[19]研究認(rèn)為RRV能上調(diào)表達(dá)UCB DCs中TLR3、TLR4，產(chǎn)生大量的下游細(xì)胞因子IL-6、IL-12/23p40、IL-10、TGF-β、TNF-α和IFN-β，誘導(dǎo)Th1類細(xì)胞反應(yīng)參與免疫應(yīng)答。除此RV感染還可能與TLR2、TLR7、TLR8和TLR9參與并誘導(dǎo)致病后的免疫應(yīng)答有關(guān)[24,25]。

TLRs通過激活下游核轉(zhuǎn)錄因子(NF-κB)和干擾素調(diào)節(jié)因子3(IFR3)等誘導(dǎo)DCs分泌細(xì)胞因子和Ⅰ型干擾素，激活固有免疫應(yīng)答[22,26]。NF-κB的活化可以誘導(dǎo)多種抗炎細(xì)胞因子的分泌，刺激初始型CD4+T和CD8+T淋巴細(xì)胞，所以RV通過改變策略抑制NF-κB活化以保證病毒的復(fù)制[22,26]。Casola等[27]認(rèn)為RV感染能誘導(dǎo)IκB激酶β(IKK-β)大量活化從而減少NF-κB基因轉(zhuǎn)錄利于RV的復(fù)制[28]。在感染初期RV可短暫地阻斷STAT1、STAT2和NF-κB的活化逃避宿主固有免疫反應(yīng)，但一些細(xì)胞因子可啟動(dòng)Jak-STAT信號(hào)途徑增強(qiáng)機(jī)體的抗RV能力[29]。與TLR2、TLR4、TLR7、TLR8屬于MyD88依賴型信號(hào)途徑不同，TLR3進(jìn)行MyD88非依賴型/TRIF依賴型的TLRs/NF-κB信號(hào)轉(zhuǎn)導(dǎo)，誘導(dǎo)NF-κB晚期活化[26]。

2.3RV感染的干擾素途徑 病毒感染可通過AMP與模式識(shí)別受體(Pattern recognition receptors，PRRs)結(jié)合，通過TLRs和RLR通路而啟動(dòng)干擾素調(diào)控因子(Interferon regulatory factor， IRF)，進(jìn)一步表達(dá)Ⅰ型IFNs(IFN-α和IFN-β)或Ⅱ型IFN(IFN-γ)參與抗病毒感染反應(yīng)[29]。IFN信號(hào)轉(zhuǎn)導(dǎo)通路主要通過啟動(dòng)JAK-STAT或PI3K、PKC、MAP激酶途徑分泌大量細(xì)胞因子產(chǎn)生抗病毒作用。NSP1與磷脂酰肌醇激酶-3(PI3K)亞基P85相互作用進(jìn)而活化抗細(xì)胞凋亡 PI3K/Akt通路，這一通路的活化有利于RV的復(fù)制[30,31]。Douagi等[32]的研究則認(rèn)為RRV和UV-treated RV均能促進(jìn)mDCs 活化和產(chǎn)生Ⅰ型IFN，RRV刺激mDCs上調(diào)表達(dá)CD40也依賴于Ⅰ型IFN信號(hào)途徑，且Ⅰ型IFN的產(chǎn)生不經(jīng)過TLR依賴信號(hào)途徑。此外RV感染后NSP1通過蛋白激酶降解IRF3、IRF5和IRF7阻斷Ⅰ型IFN轉(zhuǎn)錄，逃避宿主固有免疫反應(yīng)[33,34]。恒河猴輪狀病毒RRV和人輪狀病毒W(wǎng)a株通過抑制STAT1和STAT2的核聚集對(duì)抗天然免疫過程中Ⅰ型和Ⅱ型IFN作用[29]。Sen等[35]認(rèn)為RV通過蛋白激酶R(PKP)依賴途徑分泌IFN-β，細(xì)胞缺乏PKR會(huì)導(dǎo)致IFN-β分泌量減少，機(jī)體抗RV反應(yīng)依賴線粒體抗病毒信號(hào)蛋白(MAVS/IPS-1)、維甲酸誘導(dǎo)基因IRIG-Ⅰ、黑色素瘤分化相關(guān)基因5(MDA-5)和IRF3的參與。

最近的研究表明包括IFN-λ1(IL-29)，IFN-λ2(IL-28A)和IFN-λ3(IL-28B)的Ⅲ型IFNs也在固有免疫反應(yīng)中起著重要作用[36]。與IFN-αβ-R-/-型和野生型小鼠比較IFN-λ缺陷小鼠更易受到RV感染驗(yàn)證了上述觀點(diǎn)，成年小鼠IFN-λ表達(dá)需要完整的Tlr3/Trif信號(hào)[34]?？傊甊V感染機(jī)體Ⅰ型IFNs(IFNα/β)和Ⅲ型IFN(IFN-λ)都起著重要的抗病毒作用，它們的作用大小取決于病毒株的自然狀態(tài)、病毒復(fù)制部位、IFN-λ的協(xié)同效應(yīng)、病毒復(fù)制持續(xù)的時(shí)間及宿主的年齡等因素[37]。

2.4RV感染介導(dǎo)T細(xì)胞、B細(xì)胞免疫反應(yīng) DCs根據(jù)來源不同分為主要表達(dá)CD11c+的髓細(xì)胞來源DCs(DC1)和CD123+的漿細(xì)胞來源DCs(DC2)。DC1成熟活化后分泌大量IL-12、IL-β、IL-2α、IL-6、IL-10等促炎性細(xì)胞因子，促使CD4+T細(xì)胞向Th1分化；而DC2活化后主要分泌IL-8促使CD4+T細(xì)胞向Th2分化[38,39]，CD4+T細(xì)胞及其分泌的相關(guān)細(xì)胞因子能有效防止RV的再次感染。Jiang等[39]檢測(cè)嬰幼兒急性RV感染IL-1β、IL-2、IL-4、IL-6、IL-10、IL-12、IFN-γ、TNF-α的變化情況，結(jié)果IL-6、IL-10和IFN-γ表達(dá)量明顯增高，暗示RV自然感染時(shí)Th1和Th2類細(xì)胞因子都發(fā)揮作用且急性感染后期以IL-12和IFN-γ為主的Th1 類細(xì)胞反應(yīng)為主[40]。Wang等[41]研究認(rèn)為，Wa株RV感染細(xì)胞能誘導(dǎo)TLR4、TLR5、TLR7和TLR9基因活化并刺激下游IFN-α、IFN-β、TNF-α、IL-6、IL-8和IL-17細(xì)胞因子的表達(dá)，參與細(xì)胞免疫應(yīng)答。Narvaez等[16]的研究認(rèn)為RV感染DCs不誘導(dǎo)IDC和MDC死亡，促進(jìn)IDC分泌IL-6，但I(xiàn)L-1β、 IL-8、 IL-10、 IL-12、TNF-α、IFN-β分泌較少；MDC分泌IL-6和少量的IL-10和IL-12p70。

B細(xì)胞在抗RV感染中也起著重要作用，RV感染小鼠的脾臟和骨髓中IgG和IgA表達(dá)B細(xì)胞利于RV的清除，急性感染期黏膜B細(xì)胞也參與免疫反應(yīng)[42]。Fenaux等[40]研究發(fā)現(xiàn)，RRV感染小鼠MLN中可檢測(cè)到大量感染的B細(xì)胞和DCs,且NSP4陽性細(xì)胞能表達(dá)pDCs 標(biāo)志分子B220、mDCs 標(biāo)志分子CD11c以及CD11b。Deal等[43]的研究認(rèn)B細(xì)胞識(shí)別的Ⅰ型IFN對(duì)RV調(diào)節(jié)的B細(xì)胞活化至關(guān)重要，RV感染鼠小腸中pDCs和IFN-α/β參與B細(xì)胞活化，RV刺激的pDCs與αIFN-α共培養(yǎng)能明顯增加CD69+B細(xì)胞的表達(dá)。Pane等[44]的研究則認(rèn)為RRV感染后B細(xì)胞的活化需要CD11c+DC的參與，Ⅰ型IFN能直接增加DCs和B細(xì)胞向T細(xì)胞遞呈抗原的能力。

3 展望

綜上所述，DC通過攝取、處理、遞呈病毒粒子并產(chǎn)生相應(yīng)的免疫應(yīng)答，參與機(jī)體的抗RV感染作用。但是，病原體會(huì)通過抑制DC成熟、改變體內(nèi)DC數(shù)量、促進(jìn)DC凋亡、阻止DC遷移等多種方式逃避機(jī)體的免疫識(shí)別。隨著對(duì)RV感染免疫機(jī)制的不斷深入研究，細(xì)胞免疫和體液免疫的研究取得了巨大進(jìn)展，但對(duì)RV感染的天然免疫和腸道黏膜免疫研究相對(duì)較少。更加深入地研究RV感染與宿主細(xì)胞互作機(jī)制、RV感染對(duì)DC的影響將更全面的了解RV感染致腸炎的發(fā)病機(jī)理及抗RV感染天然免疫機(jī)制，對(duì)有效預(yù)防RV感染，促進(jìn)抗RV疫苗的研發(fā)具有重要意義。

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[收稿2016-09-03 修回2016-11-05]

(編輯 許四平)

10.3969/j.issn.1000-484X.2017.06.030

①本文受國(guó)家“863”計(jì)劃項(xiàng)目(2013AA102806)、國(guó)家自然科學(xué)基金項(xiàng)目(31272541, 31272552)和吉林省科技發(fā)展計(jì)劃項(xiàng)目(20160519011)資助。

葉麗萍(1975年-)，女，碩士，高級(jí)實(shí)驗(yàn)師，主要從事動(dòng)物微生態(tài)學(xué)與動(dòng)物黏膜免疫方面的研究，E-mail: yeliping1114@163.com。

及指導(dǎo)教師：王春鳳(1972年-)，女，博士，教授，主要從事動(dòng)物微生態(tài)學(xué)與動(dòng)物黏膜免疫方面的研究， E-mail: wangchunfeng@jlau.edu.cn。

S852.65+9.4

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1000-484X(2017)06-0947-04