CN101942013B - 乙肝病毒核心抗原和e抗原的HLA-DR9限制性调节性T细胞表位及其应用 - Google Patents
乙肝病毒核心抗原和e抗原的HLA-DR9限制性调节性T细胞表位及其应用 Download PDFInfo
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Abstract
本发明公开了一种乙肝病毒核心抗原和e抗原的HLA-DR9限制性调节性T细胞表位，由以下氨基酸序列组成：SRDLVVNYVNTNMGLKIRQLLWFHI；还公开了该调节性T细胞表位在制备包含乙肝病毒核心抗原和/或e抗原的乙肝治疗性疫苗中的应用，即在制备包含乙肝病毒核心抗原和/或e抗原的乙肝治疗性疫苗时，应从乙肝病毒核心抗原和/或e抗原中剔除具有免疫抑制作用的该调节性T细胞表位；本发明为高效乙肝治疗性疫苗的研制提供了新的策略和方法，有望打破乙肝免疫耐受，重建细胞免疫功能，高效抑制和清除乙肝病毒。
Description
技术领域
本发明涉及一种调节性T细胞(Treg)表位，特别涉及乙肝病毒核心抗原(HBcAg)和乙肝病毒e抗原(HBeAg)的HLA-DR9限制性Treg表位，还涉及该Treg表位的应用。
背景技术
乙型肝炎病毒(HBV)感染呈全球范围广泛流行，严重威胁人类健康。抗HBV特异性免疫应答对于机体清除HBV起着决定性作用。多项研究报道：在急性HBV感染的恢复者体内检测到活跃的病毒特异性CD4+和CD8+T细胞应答，而在慢性HBV感染(CHB)患者中仅观察到微弱的病毒特异性T细胞应答。CD4+CD25+Foxp3+Treg被证实能抑制其它CD4+T细胞和CD8+T细胞的活化和增殖，在维持正常的外周免疫耐受中发挥重要作用。目前研究显示，CHB患者体内Treg频率显著增高并能够通过抑制抗HBV特异性T细胞免疫应答影响病毒的清除，且病毒复制活跃的CHB患者体内有着更高比例的Treg。HBeAg阳性患者的外周血中Treg的比例显著高于HBeAg阴性患者。但导致CHB患者体内Treg频率异常改变的原因，目前尚不明确。
抗原对于诱导和维持Treg是至关重要的。因此，Treg抗原特异性研究备受关注。文献报道，从新鲜黑色素瘤组织浸润淋巴细胞中分离出的Treg具有肿瘤抗原特异性，并从相关肿瘤抗原中鉴定出若干优势性Treg表位。用源于丙型肝炎病毒(HCV)核心蛋白的交叠11肽库刺激HCV感染患者外周血单个核细胞(PBMC)，可以迅速诱导CD4+CD25highFoxp3highIFN-γ-Treg上调，而用相同肽库刺激健康者PBMC后，不能观察到CD25和Foxp3的表达上调。这些研究结果均提示疾病相关性Treg可由疾病相关抗原诱导产生。因此，明确疾病相关抗原 中潜在的Treg表位，无论对于疾病的发病机制研究还是制定更为有效的特异性免疫干预策略均有重要意义。但来源于HBV的蛋白抗原如HBcAg、HBeAg等是否参与了CHB相关性Treg的诱导和维持及其相关的Treg表位，目前尚未见报道。
发明内容
有鉴于此，本发明的目的之一在于明确HBV的蛋白抗原HBcAg和HBeAg中是否存在Treg表位及其氨基酸序列；目的之二在于提供该Treg表位的应用。
为达到上述目的，本发明采用如下技术方案：
由于HBeAg和HBcAg具有70％的共同序列，血清中的HBeAg可以看作是HBcAg的分泌型，因此，本发明先采用生物信息学方法对HBcAg和HBeAg共同序列中潜在的主要组织相容性复合体(MHC)Ⅱ类分子限制性T细胞表位热区进行预测，并合成系列候选表位肽，再用各候选表位肽分别刺激CHB患者PBMC，建立系列肽特异性T细胞系，最后通过对肽特异性T细胞系进行表型和功能检测，判断其是否具有Treg特性，以此来推断相应候选表位肽是否为Treg表位。研究结果显示，HBcAg81-105/HBeAg110-134(氨基酸序列为SRDLVVNY-VNTNMGLKIRQLLWFHI，SEQ ID No.3)能够特异性上调HLA-DR9+CHB患者PBMC中CD4+CD25+Foxp3+IL-10+Treg频率，且该群细胞具有典型的Treg细胞表型和抑制性功能，因此，HBcAg81-105、HBeAg110-134分别为HBcAg、HBeAg的HLA-DR9限制性Treg表位。
上述研究结果提示，HBV的蛋白抗原HBcAg和HBeAg中的确存在能够特异性诱导Treg的表位而导致HBV免疫抑制。该Treg表位在制备包含HBcAg和/或HBeAg的乙肝治疗性疫苗时有重要应用，即在制备包含HBcAg和/或HBeAg的乙肝治疗性疫苗时，应该摒弃HBcAg和/或HBeAg中具有免疫抑制作用的Treg表位，仅保留对免疫保护有利的表位，从而打破HBV免疫耐受，重建细胞免疫功能，高效抑制和清除HBV。
本发明的有益效果在于：本发明鉴定了HBV的蛋白抗原HBcAg和HBeAg中的Treg表位，首次明确了HBV感染患者体内上调的Treg具有HBV特异性，为进一步阐明Treg参与HBV感染慢性化过程的效应机制提供了必要的理论和实验依据，同时也为高效乙肝治疗性疫苗的研制提供了新的策略和方法，有望打破HBV免疫耐受，重建细胞免疫功能，高效抑制和清除HBV。
附图说明
为了使本发明的目的、技术方案和优点更加清楚，下面将结合附图对本发明作进一步的详细描述，其中：
图1为流式细胞仪检测各候选表位肽诱导CHB患者PBMC 10天后CD4+CD25+Foxp3+T细胞频率；
图2为CHB患者的HLA-DR分型电泳图；
图3为流式细胞仪检测候选表位肽P3特异性诱导DR9纯合型PBMC20天后CD4+Foxp3+T细胞和CD4+Foxp3-T细胞各表型的表达(以CD4+T细胞设门)；
图4为不同刺激下CD4+T细胞系中CD4+Foxp3+IL10+T和CD4+Foxp3+IFN-γ+T细胞频率；其中，
A为10μg/ml候选表位肽P3、500U/ml白介素2(IL-2)和1μg/ml抗CD28抗体(anti-CD28)刺激下CD4+T细胞系中CD4+Foxp3+IL10+T细胞频率；
B为10μg/ml候选表位肽P3、10μg/ml抗HLA-DR抗体(anti-HIA-DR)、500U/mlIL-2和1μg/ml anti-CD28刺激下CD4+T细胞系中CD4+Foxp3+IL10+T细胞频率；
C 为10μg/ml无关对照肽TT、500U/ml IL-2和1μg/ml anti-CD28刺激下CD4+T细胞系中CD4+Foxp3+IL10+T细胞频率；
D为10μg/ml候选表位肽P3、500U/ml IL-2和1μg/ml anti-CD28刺激下CD4+T细胞系中CD4+Foxp3+IFN-γ+T细胞频率；
E为10μg/ml候选表位肽P3、10μg/ml anti-HLA-DR、500U/ml IL-2和1μg/mlanti-CD28刺激下CD4+T细胞系中CD4+Foxp3+IFN-γ+T细胞频率；
F为10μg/ml无关对照肽TT、500U/ml IL-2和1μg/ml anti-CD28刺激下CD4+T细胞系中CD4+Foxp3+IFN-γ+T细胞频率；
图5为3H-TdR法检测P3肽特异性DR9限制性CD4+Treg的抑制功能。
具体实施方式
以下将参照附图，对本发明的优选实施例进行详细的描述。实施例中所述侯选表位肽或无关对照肽、IL-2、anti-CD28、anti-HLA-DR和抗CD3抗体(anti-CD3)的浓度均指其在混合液中的终浓度。
1、泛限制性CD4+T细胞表位热区的分析及候选表位肽的合成
从表位数据库(http://www.immuneepitope.org/)中得到已有的CD4+T细胞表位，根据相关文献报道以及网上软件MHCPred(http://research.i2r.a-star.edu.sg/multipre/)和SYFPEITHI(http://www.syfpeithi.de/)预测HBcAg的Treg表位。由于HBeAg和HBcAg具有70％的共同序列，血清中的HBeAg可以看作是HBcAg的分泌型，因此，本发明以HBeAg和HBcAg共同序列中的三条肽段作为候选表位肽，并以卵白蛋白片段(OVA323-339)和破伤风毒素片段(TT947-967)作为无关对照肽。候选表位肽和无关对照肽均委托上海生工生物工程技术服务有限公司采用标准9-芴甲氧羰基(Fmoc)固相合成法合成，所得多肽经高效液相色谱法测定纯度大于90％，经质谱测定分子量与理论分子量一致。
表1候选表位肽和无关对照肽的序列
2、临床CHB患者PBMC肽诱导实验及HLA-Ⅱ类等位基因分型
(1)PBMC肽诱导实验：选取血清HBV DNA载量大于105、HBeAg阳性且近期无治疗的CHB确诊患者(编号为HBV053、HBV054、HBV057、HBV059、HBV060和HBV061)，分离PBMC，加入10μg/ml侯选表位肽或无关对照肽、500U/ml IL-2和1μg/ml anti-CD28刺激10天，用流式细胞仪检测CD4+CD25+Foxp3+T细胞频率。
结果如图1所示，HBV061、HBV059和HBV053患者PBMC用候选表位肽P3刺激后，CD4+CD25+Foxp3+T细胞频率上调最为显著，其他CHB患者无明显上调。
(2)HLA-Ⅱ类等位基因分型：采用Invitrogen全基因组提取试剂盒提取待分型CHB患者的基因组DNA，再采用HLA-Ⅱ类DRB分型板Micro SSPTMGeneric HLA Class II(DRB only)进行引物特异性聚合酶链反应(SSP-PCR)获得HLA-DR型别特异的扩增产物，最后通过电泳直接分析带型判断HLA-DR型别。
结果如表1和图2所示，HBV061、HBV059和HBV053患者均含有DR9等位基因，且其各自的PBMC用候选表位肽P3刺激后均表现出CD4+CD25+Foxp3+T细胞频率明显上调，初步提示P3肽是HLA-DR9限制性的能够特异性诱导Treg的抗原肽。
表1 CHB患者HLA-DR型别的检测结果
3、P3肽特异性DR9纯合型CD4+T细胞系的表型及功能检测
(1)表型检测
在1×106个经丝裂霉素处理的DR9纯合型PBMC中加入10μg/ml候选表位肽P3或无关对照肽TT(文献Eur.J Immunol.1989，19：2237-2242报道该TT肽为DR9限制性CD4+T细胞表位)、500U/ml IL-2和1μg/ml anti-CD28诱导20天，经丝裂霉素处理的DR9纯合型PBMC、P3肽或TT肽、anti-CD28分别在第1、7和14天补加1次，IL-2每隔3天补加1次，第20天采用流式细胞仪检测CD4+Foxp3+T细胞和CD4+Foxp3-T细胞上CD25、CD45RO、CD62L、CTLA-4、HLA-DR和GITR表型的表达。
结果如图3所示，与CD4+Foxp3-T细胞相比，CD4+Foxp3+T细胞高表达CD25、CD45RO、CD62L、CTLA-4、HLA-DR和GITR表型，与文献报道一致，符合CD4+CD25+Treg的表型。
(2)anti-HLA-DR阻断实验
在1×106个经丝裂霉素处理的DR9纯合型PBMC中加入10μg/ml候选表位肽P3或无关对照肽TT、500U/ml IL-2和1μg/ml anti-CD28诱导20天，经丝裂霉素处理的DR9纯合型PBMC、P3肽或TT肽、anti-CD28分别在第1、7和14天补加1次，IL-2每隔3天补加1次，第20天再次补加经丝裂霉素处理的DR9纯合型PBMC、P3肽或TT肽，另外P3肽组加入10μg/ml anti-HLA-DR和0.65μlGolgiStopTM，刺激5小时后检测CD4+Foxp3+IFN-γ+T细胞频率，刺激24小时后检测CD4+Foxp3+IL-10+T细胞频率。
结果如图4所示，10μg/ml P3、500U/ml IL-2和1μg/ml anti-CD28刺激DR9纯合型PBMC20天后，CD4+Foxp3+IL10+T细胞占CD4+T细胞的频率为1.26％(图4A)，同样条件下这群CD4+Foxp3+T细胞几乎不分泌IFN-γ(图4D)，加入10μg/ml anti-HLA-DR共培养，CD4+Foxp3+IL10+T细胞占CD4+T细胞的频率下降至0.36％(图4B)，说明P3肽的递呈被阻断，抑制了CD4+Foxp3+T细胞的活化，从而降低了IL-10的分泌；而10μg/ml TT、500U/ml IL-2和1μg/mlanti-CD28 刺激DR9纯合型PBMC 20天后，CD4+Foxp3+T细胞几乎不分泌IL-10，而CD4+Foxp3-IL-10+T细胞占CD4+T细胞的频率为2.84％，另CD4+Foxp3+T细胞和CD4+Foxp3-T细胞均分泌少量IFN-γ，这个结果与文献报道该TT肽为DR9限制性CD4+T细胞表位相吻合。同时，这些结果也进一步说明了DR9限制性CD4+T细胞表位与DR9限制性CD4+Treg表位在细胞因子分泌上的不同，从另一角度说明了P3肽为DR9限制性CD4+Treg表位。
4、P3肽特异性CD4+CD25+Foxp3+T细胞的抑制功能检测
在1×106个经丝裂霉素处理的DR9纯合型PBMC中加入10μg/ml候选表位肽P3或无关对照肽TT、500U/ml IL-2和1μg/ml anti-CD28诱导20天，磁珠分选出CD4+CD25+T细胞；取5×104个同一患者新鲜分离的CD4+CD25-T细胞，用磷酸盐缓冲液(PH 7.4)包被的1μg/ml anti-CD3刺激14小时，中断刺激，再按数量比为1∶0、1∶1、0∶1加入前述CD4+CD25+T细胞，同时加入2.5×105个经候选表位肽P3或无关对照肽TT以及丝裂霉素处理的自体PBMC，混合培养3天，检测前16小时加入H-胸腺嘧啶核苷(3H-TdR)1μCi，在液闪计数仪上测定每分钟放射活性(cpm值)。
结果如图5所示，携带HLA-DR9等位基因的CHB患者PBMC中的确存在P3特异性的CD4+CD25+Treg，该群细胞能被P3肽特异性活化并发挥显著的抑制其他细胞增殖的功能，而同样是HLA-DR9限制性的TT肽则不能活化这一群CD4+CD25+Treg。
最后说明的是，以上实施例仅用以说明本发明的技术方案而非限制，尽管通过参照本发明的优选实施例已经对本发明进行了描述，但本领域的普通技术人员应当理解，可以在形式上和细节上对其作出各种各样的改变，而不偏离所附权利要求书所限定的本发明的精神和范围。
Claims (1)
1.乙肝病毒核心抗原和e抗原的HLA-DR9限制性调节性T细胞表位，其特征在于：由以下氨基酸序列组成：SRDLVVNYVNTNMGLKIRQLLWFHI。
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