IL2RA(CD25)：CD4+CD25+Tregs亞群最特異性標(biāo)志物，抑制效應(yīng)T細(xì)胞，免疫領(lǐng)域熱點(diǎn)分子！
日期：2023-08-17 13:27:28
2023年8月8日，信達(dá)生物在Nature Cancer期刊發(fā)表了題為“IL-2Rα-biased agonist enhances antitumor immunity by invigorating tumor-infiltrating CD25+CD8+ T cells”文章 [1]。該報(bào)道揭示了抗PD-1/IL-2雙特異性抗體融合蛋白（IBI363）的早期臨床前核心機(jī)制研究結(jié)果。數(shù)年來，隨著對(duì)T細(xì)胞亞群的不斷研究，一群能夠主動(dòng)維持免疫平衡和外周免疫耐受的細(xì)胞被發(fā)現(xiàn)，定義為調(diào)節(jié)性細(xì)胞（Tregs）。T細(xì)胞具有異質(zhì)性，包括CD4+CD25+Tregs，CD8+CD25+Tregs，CD8+CD28+Tregs細(xì)胞等，其中CD4+CD25+Tregs是目前研究最多的亞群之一。
IL2通過IL2受體αβγ三聚體誘導(dǎo)激活CD4+CD25+Tregs。CD4+CD25+Tregs細(xì)胞是一種負(fù)向免疫調(diào)控細(xì)胞，在抑制自身免疫性疾病的進(jìn)展、控制潛在有害的炎性反應(yīng)及維持自身免疫穩(wěn)態(tài)等方面起了關(guān)鍵性的作用。通過調(diào)節(jié)CD4+CD25+Tregs細(xì)胞數(shù)量，影響效應(yīng)T細(xì)胞功能，可治療多種免疫疾病或腫瘤。目前，IL2RA（CD25）作為該亞群的最特異性標(biāo)志，成為免疫調(diào)節(jié)研究領(lǐng)域的熱點(diǎn)分子！
1. 什么是CD4+CD25+調(diào)節(jié)性T細(xì)胞？
CD4+CD25+調(diào)節(jié)性T細(xì)胞（CD4+CD25+Tregs））是一類特定亞群的CD4+T細(xì)胞。它們特征性的表達(dá)CD25分子，即IL-2受體α鏈（IL-2RA），屬于職業(yè)抑制性T細(xì)胞。1995年，Sakaguchi等人首次報(bào)道在正常人和小鼠外周血及脾臟組織的CD4+T淋巴細(xì)胞中，有一細(xì)胞亞群持續(xù)高表達(dá)CD25分子，進(jìn)而首次分離出CD4+CD25+T細(xì)胞。目前該亞群特異性的標(biāo)志分子還包括FOXP3，其次CTLA-4、GXTR等，這些標(biāo)志有助于將CD4+CD25+Tregs從活性T細(xì)胞、效應(yīng)性T細(xì)胞和記憶性T細(xì)胞中區(qū)分出來。CD4+CD25+Tregs具有兩大核心功能特性：一是免疫無能性，即不響應(yīng)IL-2等刺激；二是免疫抑制性，可以抑制效應(yīng)T細(xì)胞增殖，并影響其細(xì)胞因子產(chǎn)生（圖1） [2-6]。
圖1. CD25參與Tregs調(diào)節(jié)性T細(xì)胞的發(fā)育和免疫調(diào)節(jié) [2]
2. 什么是IL2Rα/IL2RA（CD25）？
IL2Rα/IL2RA（又稱為CD25）是白細(xì)胞介素2（IL-2）受體的α鏈，其胞漿區(qū)域較短，屬于一種低親和性的白介素-2（IL-2）受體。IL-2RA因?yàn)榭梢猿掷m(xù)、高水平的表達(dá)在靜止以及活化的調(diào)節(jié)性T細(xì)胞上，所以是目前最常用的調(diào)節(jié)性T細(xì)胞標(biāo)記分子。IL-2Rβ（CD122）和IL-2Rγ（CD132）的二聚體形式是IL-2信號(hào)通路的必須結(jié)構(gòu)，但僅有IL-2Rβ和IL-2Rγ的二聚體形式存在時(shí)，IL-2無法有效的通過IL-2受體復(fù)合物信號(hào)通路調(diào)節(jié)T細(xì)胞增生。因此，IL-2Rα可以與IL-2受體的β鏈（CD122）和γ鏈（CD132）形成復(fù)合物，從而增強(qiáng)IL-2與受體的親和力（圖2） [7-11]。
IL2RA（CD25）主要表達(dá)于CD4+細(xì)胞膜表面，參與調(diào)節(jié)性CD4+T細(xì)胞在IL-2的生理低水平下進(jìn)行分化和增殖。近些年，CD4+CD25+Tregs細(xì)胞亞型，因其具有獨(dú)特的作用方式和功能特征引起了國(guó)內(nèi)外研究者的共同關(guān)注。在CD4+CD25+Tregs細(xì)胞中，CD25作為IL-2受體的關(guān)鍵組成部分，使Treg細(xì)胞能夠響應(yīng)IL-2信號(hào)，發(fā)揮免疫調(diào)控功能。Treg細(xì)胞通過抗原非特異性機(jī)制來抑制效應(yīng)T細(xì)胞的激活。總之，IL-2RA（CD25）作為Treg細(xì)胞的重要標(biāo)志，不僅標(biāo)識(shí)了這個(gè)特定的細(xì)胞亞群，還使CD4+CD25+Tregs能夠發(fā)揮關(guān)鍵的免疫調(diào)控功能 [7-11]。
圖2. IL-2與IL-2α、β和γ鏈?zhǔn)荏w復(fù)合物結(jié)構(gòu)示意圖 [11]
3. IL2RA相關(guān)的調(diào)控機(jī)制
3.1 IL2/IL2Rα信號(hào)通路機(jī)制
IL2Rα作為IL-2異源三聚體受體復(fù)合物的α鏈，與IL-2受體β鏈、γ鏈形成IL-2受體復(fù)合物。IL-2受體復(fù)合物本身不具有激活信號(hào)通路能力，是通過與非受體型蛋白酪氨酸激酶偶聯(lián)，激活下游信號(hào)傳導(dǎo)通路。主要通過以下三條信號(hào)通路傳導(dǎo) （圖3）[12-14]：
i) Jak-STAT途徑。激酶被激活，IL-2R胞內(nèi)段Jak蛋白結(jié)合部分發(fā)生磷酸化，啟動(dòng)STAT因子轉(zhuǎn)入細(xì)胞核中，使靶基因發(fā)揮調(diào)控細(xì)胞增殖與凋亡的作用。
ii) MAP激酶途徑。激酶和Syk激酶活化后，使IL-2R胞內(nèi)段發(fā)生磷酸化，引發(fā)Shc蛋白和Grb-2蛋白級(jí)聯(lián)激活，使具有絲氨酸/蘇氨酸蛋白激酶活性的Raf-1蛋白啟動(dòng)MAP激酶途徑；另外，在Jak激酶活化后還可以激動(dòng)Pyk2激酶，從而啟動(dòng)MAP激酶途徑；最終調(diào)節(jié)細(xì)胞周期蛋白依賴激酶對(duì)特定底物發(fā)揮作用，促進(jìn)細(xì)胞增殖。
iii) 磷酸酰肌醇-3-激酶PI3K途徑。該過程需要Jak激酶、Pyk2激酶的參與，lck激酶作為啟動(dòng)因子，磷酸酰肌醇-3-激酶與Shc蛋白結(jié)合后刺激致癌基因Akt和p70S6k表達(dá)，參與調(diào)控細(xì)胞凋亡及增殖活動(dòng)。
圖3. IL-2/IL-2Rα信號(hào)通路機(jī)制 [12]
3.2 CD4+CD25+Tregs的免疫負(fù)調(diào)節(jié)機(jī)制
IL2RA（CD25）作為Treg細(xì)胞的重要標(biāo)志，不僅標(biāo)識(shí)了CD4+CD25+Tregs這個(gè)特定的細(xì)胞亞群，還使其能夠發(fā)揮關(guān)鍵的免疫調(diào)控功能。CD25分子在CD4+CD25+ Treg上呈高表達(dá)狀態(tài)，能夠與效應(yīng)細(xì)胞競(jìng)爭(zhēng)性結(jié)合IL-2，使效應(yīng)細(xì)胞無法得到生長(zhǎng)信號(hào)而不能增殖。CD4+CD25+Tregs細(xì)胞的主要功能特性是免疫無能性和免疫抑制性。免疫無能性是指在抗原刺激下，Treg呈現(xiàn)無反應(yīng)狀態(tài)，即使在高濃度IL-2單獨(dú)刺激下也呈無應(yīng)答狀態(tài)。免疫抑制性是指在T細(xì)胞受體（TCR）介導(dǎo)的信號(hào)刺激下，調(diào)節(jié)性T細(xì)胞可活化、增殖成為有抑制作用的T淋巴細(xì)胞 [13-14]。
近年來體內(nèi)外研究表明，除了IL-2RA（CD25），細(xì)胞因子（IL-10、TGF-β、IL-2、IL-6）和某些細(xì)胞膜分子（CTLA-4、GITR）也在CD4+CD25+Tregs功能的發(fā)揮中起了一定的作用 （圖4）[15-18]。目前對(duì)CD4+CD25+Tregs的效應(yīng)機(jī)制還不十分明確。最初的體外研究明確支持CD4+CD25+Tregs是通過與其他細(xì)胞直接接觸發(fā)揮抑制作用這一觀點(diǎn)。因此，細(xì)胞-細(xì)胞互相接觸是該亞型發(fā)揮作用的先決條件。
圖4. IL-10和TGF-β參與CD4+CD25+Treg（iTREG）的免疫調(diào)節(jié)作用機(jī)制 [16]
4. CD4+CD25+Tregs在多種疾病中的作用
IL2RA，即DC25，主要表達(dá)于CD4+CD25+Tregs細(xì)胞表面。CD4+CD25+Tregs作為新近發(fā)現(xiàn)的，一個(gè)具有獨(dú)特免疫調(diào)節(jié)作用的T細(xì)胞亞群，其在維持機(jī)體免疫耐受和調(diào)節(jié)免疫反應(yīng)中起著重要作用！隨著研究的深入，該亞型逐漸成為最近幾年來研究的熱點(diǎn)。
4.1 CD4+CD25+Tregs與自身免疫性疾病
目前已有大量的證據(jù)表明CD4+CD25+Tregs細(xì)胞數(shù)量和或功能異常是打破自身免疫耐受與誘發(fā)許多自身免疫性疾病的重要因素。與正常人相比I型糖尿病患者的外周血中CD4+CD25+Tregs細(xì)胞數(shù)量均明顯降低，并且與疾病的嚴(yán)重程度有關(guān)。除了數(shù)量缺少外，I型糖尿病患者的CD4+CD25+Tregs細(xì)胞的免疫抑制功能也降低。在某些情況下，這些T細(xì)胞雖然數(shù)量沒有明顯變化，但對(duì)抑制T細(xì)胞增殖的作用減少，同時(shí)分泌IFN-γ增加、分泌IL-10減少。這可能導(dǎo)致CD4+CD25+T細(xì)胞的抑制功能減弱，影響對(duì)胰島的保護(hù) [19-20]。
在系統(tǒng)性紅斑狼瘡SLE中，研究發(fā)現(xiàn)患者外周血CD4+CD25high T細(xì)胞與CD4+CD25int T細(xì)胞的比率降低，說明SLE存在免疫失衡，主要表現(xiàn)為抑制功能細(xì)胞下降，而效應(yīng)性T細(xì)胞升高。通過增加CD4+CD25high T細(xì)胞的數(shù)量和功能或抑制效應(yīng)T細(xì)胞可作為SLE治療靶點(diǎn) [21]。在另外一些自身免疫性疾病中，如多發(fā)性硬化病 [22]、類風(fēng)濕關(guān)節(jié)炎 [23]、銀屑病 [24]、Wegner’s肉芽腫病 [25]和重癥肌無力 [26]等，雖然CD4+CD25+Tregs細(xì)胞的數(shù)量正常，但其免疫抑制活性是下降的或者缺乏的。
4.2 CD4+CD25+Tregs與移植物抗宿主病
CD4+CD25+Tregs在移植物抗宿主病（GVHD）中發(fā)揮重要作用。GVHD是一種免疫性疾病，常見于異種基因造血干細(xì)胞移植。研究表明，CD4+CD25+Tregs可以調(diào)節(jié)GVHD的發(fā)生。供者淋巴細(xì)胞中去除CD4+CD25+T細(xì)胞或受體中去除CD25+T細(xì)胞會(huì)增加GVHD的風(fēng)險(xiǎn)，而輸注新鮮的供體CD4+CD25+T細(xì)胞可以減輕GVHD。其中，CD4+CD25+CD62L+Treg對(duì)急性GVHD的調(diào)節(jié)作用顯著。不同的CD4+CD25+Tregs亞群在抑制GVHD中的作用有所不同。這些發(fā)現(xiàn)對(duì)于GVHD的臨床預(yù)防和治療提供了有益的信息 [27-28]。
4.3 CD4+CD25+Tregs與腫瘤
許多腫瘤抗原為自身抗原，CD4+CD25+Tregs能抑制T細(xì)胞對(duì)外來和自體抗原的免疫應(yīng)答，因而在維持對(duì)自身成分耐受的同時(shí)，也會(huì)阻止機(jī)體對(duì)腫瘤細(xì)胞的免疫應(yīng)答，從而導(dǎo)致了腫瘤的免疫逃逸 [29-30]。在急性髓系白血病（acute myeloid leukemia，AML）中，CD25+AML患者的白血病細(xì)胞高表達(dá)髓系抗原CD11b、CD36；淋系抗原CD4、CD22；骨髓干細(xì)胞抗原CD123。而低表達(dá)漿細(xì)胞抗原CD38及NK細(xì)胞抗原CD56 [31-32]；在卵巢癌中，腫瘤細(xì)胞分泌CCL22，招募CD4+CD25+Tregs至腫瘤部位，導(dǎo)致CD4+CD25+Tregs在癌腫組織中聚集，而在正常的卵巢組織中幾乎不能看到CD4+CD25+Tregs。對(duì)于腫瘤而言，去除這群細(xì)胞可能有助于誘發(fā)有效的腫瘤免疫 [33-34]。
4.4 CD4+CD25+Tregs與其它疾病
CD4+CD25+Tregs的抑制作用使得幽門螺桿菌無法被免疫系統(tǒng)清除而長(zhǎng)期存在，對(duì)胃、十二指腸造成了損害，導(dǎo)致胃、十二指腸潰瘍甚至癌變 [35]；IL2RA基因的rs3118470位點(diǎn)的基因多態(tài)性與斑秀的家族史以及病情嚴(yán)重程度存在著一定的相關(guān)性 [36]；在妊娠小鼠的脾臟、回腸淋巴結(jié)以及外周血中，CD4+CD25+Tregs的比例明顯高于非妊娠對(duì)照組小鼠。如果將抗CD25單抗克隆體輸注給小鼠，則會(huì)導(dǎo)致其流產(chǎn)。說明CD4+CD25+Tregs在誘導(dǎo)母胎免疫耐受方面起著重要作用 [37]。
在大鼠腦缺血再灌注CD4+CD25+Tregs細(xì)胞輸注移植治療模型中，CD4+CD25+Tregs細(xì)胞可以減小大腦中動(dòng)脈阻塞缺血再灌注（MCAO/R）大鼠腦梗死體積，降低缺血后神經(jīng)功能缺損，提高神經(jīng)功能恢復(fù)。此外，CD4+CD25+Tregs細(xì)胞還可降低缺血對(duì)寡突膠質(zhì)細(xì)胞和軸突造成的損害，減輕腦缺血后白質(zhì)損傷 [38]。
5. IL2RA的臨床研究前景
目前，有多家機(jī)構(gòu)在研究靶向IL-2RA（CD25）的藥物，包括三生國(guó)健藥業(yè)（上海）股份有限公司、信達(dá)生物、Ligand Pharmaceuticals, Inc.、Eisai Co., Ltd.和Novartis Pharma AG等。三種靶向CD25/IL-2RA的藥物已經(jīng)獲得批準(zhǔn)上市，分別是Daclizumab達(dá)克珠單抗和Basiliximab巴利昔單抗（均用于腎移植排斥反應(yīng)）、Denileukin Diftitox地尼白介素2（用于外周T細(xì)胞淋巴瘤和轉(zhuǎn)移性黑色素瘤）。此外，還有一些藥物正在進(jìn)行臨床試驗(yàn)，如Inolimomab伊諾莫單抗已處于批準(zhǔn)上市階段，用于移植物抗宿主病GVHD。CD4+CD25+Tregs作為一個(gè)具有免疫調(diào)節(jié)作用的T淋巴細(xì)胞亞群，對(duì)它的研究正步入到一個(gè)新階段！因此，對(duì)Treg細(xì)胞最特異性標(biāo)志IL-2RA（CD25）作用的深入研究將有助于對(duì)機(jī)體免疫調(diào)節(jié)機(jī)制的了解，最終為相關(guān)疾病的治療開辟新的免疫治療途徑。
為鼎力協(xié)助科研和藥企人員針對(duì)IL-2RA（CD25）在多種免疫疾病和腫瘤中的臨床應(yīng)用研究，CUSABIO推出IL-2RA（CD25）活性蛋白（Code: CSB-MP011649HU3），助力您在IL-2RA（CD25）機(jī)制方面的研究或其潛在臨床價(jià)值的探索。
IL-2RA（CD25）蛋白
by SDS-PAGE
Purity was greater than 95% as determined by SDS-PAGE.(Tris-Glycine gel) Discontinuous SDS-PAGE (reduced) with 5% enrichment gel and 15% separation gel.
Immobilized Human IL2RA at 2μg/mL can bind Anti-IL2RA recombinant antibody (CSB-RA011649MA1HU)，the EC50 is 2.463-3.353 ng/mL.
Immobilized Human IL2RA at 2μg/mL can bind Human IL2 (CSB-MP011629HU)，the EC50 is 1.693-2.039 ng/mL.
參考文獻(xiàn)：
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