γδ T細(xì)胞抗人類免疫缺陷病毒感染作用的研究進展

何璇，梁華，邵一鳴

中國疾病預(yù)防控制中心性病艾滋病預(yù)防控制中心，北京 102206

自1981年確認(rèn)首例艾滋病患者以來，艾滋病已迅速擴散至世界范圍，成為威脅人類健康的重大傳染病之一。抗病毒感染的第1道防線——天然免疫已日趨成為研究熱點。γδ T 細(xì)胞作為天然免疫的重要組分，在抗人類免疫缺陷病毒(human immunodeficiency virus，HIV)的天然免疫甚至獲得性免疫中發(fā)揮了重要作用。

T細(xì)胞依據(jù)T細(xì)胞受體 (T cell receptor，TCR)的不同，分為αβ T細(xì)胞和γδ T細(xì)胞。與αβ T細(xì)胞不同，γδ T細(xì)胞不表達CD4和CD8，無需主要組織相容性復(fù)合物(major histocompatibility complex，MHC)限制即可直接識別抗原而發(fā)揮作用。γδ T 細(xì)胞主要分2個亞群：Vδ1亞群，集中分布于上皮組織中，可能參與呼吸道、腸道等黏膜免疫[1-4]；Vδ2亞群，為外周血的主要γδ T細(xì)胞亞群，其中Vγ2Vδ2 亞型(也稱Vγ9Vδ2)是主要循環(huán)細(xì)胞，占血液T細(xì)胞的1%～5%，在抗微生物感染和抗腫瘤免疫方面發(fā)揮作用。已有多項研究表明，γδ T細(xì)胞不但可以直接識別并殺傷靶細(xì)胞，參與早期抗HIV的天然免疫，而且其分泌的各類細(xì)胞因子及抗原呈遞細(xì)胞(antigen-presenting cell, APC)有助于誘發(fā)獲得性免疫反應(yīng)[5]。

1 γδ T細(xì)胞激活

1.1 TCR介導(dǎo)的激活

Vγ9Vδ2 T細(xì)胞表面的TCR能直接識別低相對分子質(zhì)量的非肽抗原，而無需抗原呈遞[6]。在HIV感染中，HIV復(fù)制能改變細(xì)胞代謝途徑，從而增加并釋放中間產(chǎn)物phosphometabolite (PM)，使Vγ9Vδ2 T細(xì)胞持續(xù)激活。異戊烯焦磷酸單酯 (isopentenyl pyrophosphate，IPP) 是較常見的磷酸類抗原，為真核細(xì)胞中甲羥戊酸-膽固醇代謝途徑的中間產(chǎn)物，識別病變細(xì)胞或感染細(xì)胞釋放的危險信號[7]，常用作Vγ9Vδ2 T細(xì)胞體外功能檢測的刺激劑。此外，體外實驗中Vγ9Vδ2 T細(xì)胞還能被一些非磷酸類物質(zhì)激活，如烷基胺(alkylamine)、Ecto-F1-ATP合成酶(Ecto-F1-ATPase)[8]等。另外，有研究表明，Vγ9Vδ2 T細(xì)胞還能識別熱休克蛋白(heat shock protein，HSP)家族中的成員，這些蛋白可能是病變細(xì)胞或感染細(xì)胞過度表達的產(chǎn)物[1,9]。

1.2 共刺激分子介導(dǎo)的激活

除通過TCR識別非肽抗原外，γδ T細(xì)胞表面其他分子也參與γδ T細(xì)胞的激活，這類分子稱為“共刺激分子”(co-receptor)。包括4類：黏附配體(adhesion partner molecule)、Toll樣受體(Toll-like receptor，TLR)、天然殺傷受體(natural killer receptor，NKR)及Fc受體。黏附配體包括淋巴細(xì)胞功能相關(guān)抗原1(lymphocyte function-associated antigen 1，LFA-1)、胞內(nèi)黏附分子﹝如細(xì)胞間黏附分子1(intercellular adhesion molecule 1，ICAM-1)、CD2/LFA-3等﹞[10,11]。TLR屬模式分子識別受體(pattern recognition receptor，PRR)家族成員，可廣泛識別病原體相關(guān)分子模式(pathogen-associated molecular pattern，PAMP)而參與γδ T細(xì)胞激活。如TLR3可使已被TCR激活的Vγ9Vδ2 T細(xì)胞上調(diào)一些基因，表達與細(xì)胞毒作用相關(guān)的蛋白[12,13]。大多數(shù)γδ T細(xì)胞，尤其是具細(xì)胞毒功能的Vγ9Vδ2 T細(xì)胞中有表達活化NKR(activating NKR，aNKR)和抑制NKR(inhibitory NKR，iNKR)的作用。這2種受體之間的平衡作用直接影響γδ T細(xì)胞功能。aNKR+γδ T細(xì)胞能識別MHCⅠ類缺陷細(xì)胞，如K562和Daudi細(xì)胞系，而發(fā)揮細(xì)胞殺傷效應(yīng)，其殺傷機制稱為“missing self”假說[14]。γδ T細(xì)胞中iNKR具有抑制受體的功能，與各種人類白細(xì)胞抗原(human leukocyte antigen，HLA)Ⅰ類分子結(jié)合后，啟動殺傷細(xì)胞阻止信號，從而參與控制TCR介導(dǎo)的對保守自身抗原和外源性配體的免疫反應(yīng)[15]。此外，NKR還協(xié)助Vδ2 T細(xì)胞穿越內(nèi)皮細(xì)胞層[16]。與NK細(xì)胞一樣，Vγ9Vδ2 T細(xì)胞也能表達FcγRⅢ(CD16)，且CD16的表達與Vγ9Vδ2 T細(xì)胞的效應(yīng)細(xì)胞分化相關(guān)[17]，并直接介導(dǎo)Vγ9Vδ2 T細(xì)胞發(fā)揮抗體依賴細(xì)胞介導(dǎo)的細(xì)胞毒性(antibody-dependent cell-mediated cytotoxicity，ADCC)作用。

2 γδ T細(xì)胞與HIV的相互作用

2.1 γδ T細(xì)胞在抗HIV感染中的作用

γδ T細(xì)胞亞群根據(jù)表達的TCR不同，有不同的分布和功能。存在于外周血中的Vδ2 T細(xì)胞具細(xì)胞毒作用，能產(chǎn)生大量γ干擾素(interferon γ，IFN-γ)和腫瘤壞死因子α(tumor necrosis factor α，TNF-α)；而存在于組織中的Vδ1 T細(xì)胞細(xì)胞毒作用較小，主要產(chǎn)生各種細(xì)胞因子，包括白細(xì)胞介素4(interleukin 4，IL-4)和IL-17[18,19]。當(dāng)受抗原刺激時，γδ T細(xì)胞的2個細(xì)胞群表達與各自功能相關(guān)的趨化受體，可轉(zhuǎn)移到胞外組織的炎癥部位，發(fā)揮抗感染作用。激活后的γδ T細(xì)胞表達CC趨化因子受體7(chemokine CC motif receptor 7，CCR7)，遷移到淋巴結(jié)，發(fā)揮抗HIV感染作用[20]。黏膜 Vγ9Vδ2 T細(xì)胞可在抗HIV感染早期發(fā)揮一定作用。恒河猴口腔注射猴免疫缺陷病毒(simian immunodeficiency virus，SIV)后，在較短時間內(nèi)便可觀察到隨淋巴結(jié)歸巢受體表達增加黏膜γδ T細(xì)胞顯著增加[21]。

HIV感染期間，Vγ9Vδ2 T細(xì)胞通過非特異地識別HIV，直接或間接發(fā)揮抗病毒功能?；罨蟮腣γ9Vδ2 T細(xì)胞能分泌Th1類細(xì)胞因子，包括TNF-α、 IFN-γ。體外實驗中，經(jīng)IPP刺激的Vγ9Vδ2 T細(xì)胞在4～12 h便可產(chǎn)生巨噬細(xì)胞炎性蛋白1α(macrophage inflammatory protein 1α，MIP-1α)、MIP-1β和淋巴細(xì)胞趨化因子(lymphotactin)[22]。同時，Vγ9Vδ2 T細(xì)胞還能表達多種β類趨化因子受體，包括CCR1、CCR5和CCR8[23]。另外，它們同NK細(xì)胞一樣，在“missing self”機制下，通過分泌穿孔素、顆粒酶或Fas/FasL凋亡途徑發(fā)揮細(xì)胞毒作用，直接殺傷HIV感染細(xì)胞[24-26]。在靈長類動物實驗中，受IL-2刺激擴增后的γδ T細(xì)胞能直接溶解SIV感染的靶細(xì)胞，殺傷機制與NK細(xì)胞相似[27]。這與Vγ9Vδ2 T細(xì)胞表達NK細(xì)胞類似受體有關(guān)。其次，激活的Vγ9Vδ2 T細(xì)胞能通過與HIV競爭CCR5共刺激分子或釋放抗病毒因子而阻止HIV復(fù)制[28,29]。在SIV黏膜感染恒河猴體內(nèi)發(fā)現(xiàn)黏膜部位的γδ T細(xì)胞也具有類似功能[30]。除直接殺傷外，Vγ9Vδ2 T細(xì)胞可通過CD16行使ADCC作用。Poonia等發(fā)現(xiàn)在HIV感染精英控制者中，表達CD16的Vγ9Vδ2 T細(xì)胞群被高度激活。體外實驗證實，這些細(xì)胞可能通過ADCC作用殺傷被Env包被的靶細(xì)胞[31]。

除自身活化后發(fā)揮直接抗病毒感染免疫應(yīng)答外，γδ T細(xì)胞還能協(xié)助其他細(xì)胞激活和趨化。HIV感染后，激活的Vγ9Vδ2 T細(xì)胞產(chǎn)生大量前炎癥細(xì)胞因子和趨化因子，可協(xié)助中性粒細(xì)胞、巨噬細(xì)胞以及T細(xì)胞募集[32,33]。與Th17相似，Vγ9Vδ2 T細(xì)胞可通過釋放單核細(xì)胞趨化蛋白2(monocyte chemoattractant protein 2，MCP-2)激活中性粒細(xì)胞，在HIV感染早期對防止胃腸黏膜中病毒擴散發(fā)揮重要作用[34]。另外，激活的Vγ9VδT細(xì)胞能誘導(dǎo)樹突細(xì)胞成熟和活化，表明Vγ9Vδ2 T細(xì)胞可能具有佐劑作用，可增強抗原特異性αβ T細(xì)胞反應(yīng)[35,36]。Vγ9Vδ2 T細(xì)胞與單核細(xì)胞相互作用能激活Th17，使中性粒細(xì)胞激活，并轉(zhuǎn)移到炎癥部位后發(fā)生反應(yīng)[37]。以上研究表明，Vγ9Vδ2 T細(xì)胞與其他免疫細(xì)胞相互作用，直接參與早期抗微生物感染的免疫應(yīng)答。γδ T細(xì)胞也具有一定的免疫調(diào)節(jié)作用。HIV感染者血清中新嘌呤和β2微球蛋白含量增加，與腸上皮淋巴細(xì)胞中大量存在的γδ T細(xì)胞呈負(fù)相關(guān)，表明腸上皮γδ T細(xì)胞具有限制非特異性免疫過度反應(yīng)的能力[38]。

抗原刺激后的Vγ9Vδ2 T細(xì)胞具有APC功能，能上調(diào)MHCⅠ類和Ⅱ類分子表達。另外，共刺激分子CD40、CD83的表達增加也表明，γδ T細(xì)胞具有吞噬細(xì)胞、呈遞抗原以及激活αβ T細(xì)胞的能力[39,40]。上述研究結(jié)果均為體外研究，γδ T細(xì)胞在體內(nèi)如何行使APC功能還有待進一步研究。

2.2 HIV感染對γδ T細(xì)胞的影響

多項研究結(jié)果表明，Vγ9Vδ2 T細(xì)胞與HIV感染疾病進展有直接關(guān)系。與正常人相比，HIV感染者外周血中Vδ2 T細(xì)胞/Vδ1 T細(xì)胞比例明顯倒置[41]，原因包括Vδ2 T細(xì)胞丟失和外周血中Vδ1 T細(xì)胞增加。有證據(jù)表明，Vγ9Vδ2 T細(xì)胞的丟失與病毒載量相關(guān)：性傳播途徑感染的HIV感染者，隨著HIV載量反彈，循環(huán)Vγ9Vδ2 T細(xì)胞丟失加重[42]。Li等通過研究146例血液污染事件中的HIV感染者，發(fā)現(xiàn)Vγ9Vδ2 T細(xì)胞數(shù)量與病毒載量呈顯著負(fù)相關(guān)，與CD4 T細(xì)胞數(shù)呈正相關(guān)[43]。該研究隨訪人群數(shù)量多，HIV感染時間和亞型基本一致，更加明確證實了Vγ9Vδ2 T 細(xì)胞數(shù)量減少與慢性HIV感染者的疾病進展緊密相關(guān)。而Vδ1 T細(xì)胞擴增與病毒載量升高呈正相關(guān)，并可能通過HIV消耗CD4+T細(xì)胞[44]。在HIV感染者血清中發(fā)現(xiàn)，HIV Tat蛋白能干擾IFN-γ誘導(dǎo)蛋白10(IFN-γ-inducible protein 10，IP-10)/CXCL10、6Ckine/SLC/CCL21等的趨化活性[45]，這很可能是γδ T細(xì)胞2個亞群在HIV感染者中分布發(fā)生變化的原因。另一研究結(jié)果也證實，Vδ1 T細(xì)胞數(shù)增加可能并不是針對HIV感染克隆擴增的結(jié)果，而是受趨化因子的影響，Vδ1 T細(xì)胞從各種組織中滲透到外周血中[34]。Vγ9Vδ2 T細(xì)胞丟失則可能是由于HIV入侵后，誘導(dǎo)細(xì)胞表面Fas表達增高，與Vγ9Vδ2 T細(xì)胞表面的FasL相互作用，使Vγ9Vδ2 T 細(xì)胞凋亡[46]。有趣的是，Riedel等發(fā)現(xiàn)HIV精英控制者能較好地維持Vδ2 T細(xì)胞數(shù)目，其Vδ2 T細(xì)胞數(shù)目甚至高于健康人[47]，再次證實Vγ9Vδ2 T細(xì)胞在控制HIV感染方面起重要作用。

以上研究結(jié)果均顯示，HIV復(fù)制直接影響Vγ9Vδ2 T細(xì)胞內(nèi)環(huán)境的穩(wěn)定。Vγ9Vδ2 T細(xì)胞在HIV復(fù)制期激活，當(dāng)病毒血癥無法控制時迅速丟失，在艾滋病進展期以及HIV病毒血癥患者中丟失更為嚴(yán)重。由于HIV感染對γδ T細(xì)胞亞群有如此大的影響，且丟失細(xì)胞主要是Vδ2 T細(xì)胞亞群(包含大多數(shù)功能性細(xì)胞，即針對磷酸化抗原起反應(yīng)的γδ T細(xì)胞[48])，提示該途徑可能是HIV在感染初期逃逸免疫系統(tǒng)的策略之一：降低功能性細(xì)胞群數(shù)量，從而逐步瓦解免疫系統(tǒng)。

除了數(shù)量和分布，HIV感染還影響γδ T細(xì)胞功能。HIV感染者體內(nèi)存留的Vγ9Vδ2 T細(xì)胞在TCR刺激后無法擴增，也無功能性反應(yīng)，如IFN-γ、TNF-α的分泌或IL-2受體的表達[49,50]。在HIV感染不同階段，通過檢測HLA-D相關(guān)表達，發(fā)現(xiàn)CD4+T細(xì)胞數(shù)與Vγ9Vδ2 T細(xì)胞激活呈負(fù)相關(guān)[51]。HIV感染早期引起大量細(xì)胞因子如IL-15、IFN-α、TNF-α釋放[52]，這些前炎癥因子導(dǎo)致CD3ζ表達下降，這可能是γδ T細(xì)胞無功能的原因[53]。這種無功能反應(yīng)也是HIV逃逸免疫系統(tǒng)的策略之一，可直接造成γδ T細(xì)胞功能不可逆性的損傷。由于猴體中Vγ9Vδ2 T細(xì)胞與人體相近，類似現(xiàn)象在SIV感染恒河猴體內(nèi)也有發(fā)現(xiàn)[54,55]。

3 γδ T細(xì)胞在臨床方面的應(yīng)用

近幾年來，研究學(xué)者逐漸意識到γδ T細(xì)胞在免疫臨床應(yīng)用中的重要作用。正如前文所說，γδ T細(xì)胞能直接識別低相對分子質(zhì)量的非肽抗原，故可利用非肽抗原激活γδ T細(xì)胞，使其發(fā)揮抗病毒感染效應(yīng)。前文已經(jīng)提到HIV感染直接影響Vγ9Vδ2 T細(xì)胞，使其數(shù)量下降，功能受損。有研究指出，接受高效抗反轉(zhuǎn)錄病毒治療(highly active antiretroviral therapy，HAART)后，尤其是HIV感染者體內(nèi)病毒血癥得到控制時，無論Vδ2 T細(xì)胞/Vδ1 T細(xì)胞比例還是Vγ9Vδ2 T細(xì)胞功能都顯著恢復(fù)[56,57]，表明γδ T細(xì)胞與抗病毒治療中病毒血癥的控制有關(guān)。如果能在HIV感染者體內(nèi)注入非肽抗原協(xié)助Vγ9Vδ2 T細(xì)胞擴增和激活，或直接將Vγ9Vδ2 T細(xì)胞回輸體內(nèi)，可能是治療HIV感染的有效方案。

控制HIV感染最有效的途徑是研制出有效的HIV疫苗。然而經(jīng)過20多年研究，依然無有效的HIV疫苗上市。現(xiàn)今，除了研究如何使用疫苗誘導(dǎo)獲得性免疫反應(yīng)外，如何協(xié)調(diào)宿主天然免疫和獲得性免疫聯(lián)合對抗HIV感染成為一個重要方向。有研究人員指出，Vγ9Vδ2 T細(xì)胞可能與淋巴壓力監(jiān)測系統(tǒng)相關(guān)[58]，它們是已激活但處于靜止?fàn)顟B(tài)的循環(huán)淋巴細(xì)胞群，無需抗原呈遞過程便能快速而有效地對危險信號進行識別，正是連接天然免疫和獲得性免疫的重要樞紐。在近期猴體實驗中，SIVgp120免疫后的恒河猴針對SIV黏膜途徑攻毒產(chǎn)生保護，其中黏膜γδ T 細(xì)胞比例有所增加，且γδ T 細(xì)胞能產(chǎn)生抗病毒因子，如調(diào)節(jié)激活正常T細(xì)胞表達和分泌因子(regulated upon activation, normal T cell expressed and secreted，RANTES)、MIP-1α 和MIP-1β[29]。因此，將γδ T細(xì)胞納入免疫激活策略，將為HIV疫苗的研制提供更多新的線索。

綜上所述，天然免疫成員γδ T細(xì)胞在抗HIV感染中起重要作用。本實驗室前期研究發(fā)現(xiàn)，在HIV慢性感染期，Vγ9Vδ2 T細(xì)胞與疾病進展極其相關(guān)[44]。然而，依然存在很多問題有待解決：在HIV感染早期，γδ T細(xì)胞開始丟失的時間和丟失機制；如何增強γδ T細(xì)胞抗HIV感染作用，即加強對HIV感染細(xì)胞的殺傷能力，使HIV擴散在感染早期得以控制。對γδ T細(xì)胞作用機制的深入研究必將促進對HIV感染與宿主免疫系統(tǒng)之間相互作用的了解，進而為抗HIV感染藥物、抗病毒免疫制劑以及HIV疫苗的研究提供科學(xué)依據(jù)和研究方向。

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