CN111875698B - 靶向hcmv的tcr及其获得方法和应用 - Google Patents
靶向hcmv的tcr及其获得方法和应用 Download PDFInfo
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Abstract
本发明涉及一种靶向HCMV的TCR，属于细胞免疫治疗技术领域。所述TCR包括α链的CDR1、CDR2和CDR3可变域，以及β链的CDR1、CDR2和CDR3可变域，所述α链的CDR3可变域选自SEQ ID NO:1序列，所述β链的CDR3可变域选自SEQ ID NO:2序列。上述靶向HCMV的TCR，包括α链(CDR1，CDR2，CDR3)的以及β链(CDR1，CDR2，CDR3)，可将包括上述TCR的T细胞通过体外扩增并回输到病人体内，由于该T细胞能够特异性识别HCMV病毒抗原，从而重构病人对HCMV病毒的免疫功能，抑制病毒增殖并杀死被感染细胞。
Description
技术领域
本发明涉及细胞免疫治疗技术领域，特别是涉及一种靶向HCMV的TCR及其获得方法和应用。
背景技术
人巨细胞病毒(Human cytomegalovirus,HCMV)属于疱疹病毒亚科(Betaherpesvirinae)，全球80％以上人群血清检测呈现CMV阳性，且一旦被感染便会终生携带。HCMV在具有健全免疫力的健康人群中往往是无症状的，病毒的间接性复活(REF)能够被免疫系统检测并有效的控制。然而，对于免疫功能低下或者免疫功能被抑制的人群或者病人，譬如接受器官移植和造血干细胞移植的病人、艾滋病患者和正在发育中的胎儿，HCMV的感染或者复活通常会引起发病甚至造成死亡。
造血干细胞移植和器官移植往往是血癌患者和某些疾病患者的终极治疗手段，而HCMV复活是引起干细胞/器官移植手术后病毒感染综合症的主要原因之一，无法控制的病毒复制往往会造成多器官衰竭以致威胁生命。目前通常的预防措施和一线治疗手段是使用抗病毒分子抑制剂，然而这些药物本身的毒性也会对病人造成伤害；同时相当一部分病人会产生耐药性，引起HCMV再次复活。尽管HCMV疫苗的研发从1900年起就一直在进行中，但目前并没有相关疫苗获批进入临床治疗。
在被病毒感染的细胞中，病毒蛋白抗原短肽(peptide)能够结合主要组织相容性复合体(Major Histocompatibility Complex,MHC)形成p-MHC复合体，再被呈递到细胞膜表面。T细胞通过其细胞表面表达的T细胞受体(T cell receptor,TCR)，特异性的识别被感染细胞表面所呈递的抗原短肽。TCR和p-MHC的特异性结合将会激活T细胞，特异性识别、杀死表达病毒蛋白的被感染细胞，并可以在患者体内建立长期的免疫记忆。
T细胞过继性免疫治疗是将T细胞(具备能够特异性识别致病病毒抗原的TCR)通过体外扩增并回输到病人体内，从而重构病人对这种病毒的免疫功能，抑制病毒增殖并杀死被感染细胞。
TCR识别特定种类的HLA-抗原决定簇复合物并发挥功能，而人类白细胞抗原(human leukocyte antigen,HLA)在人群中具备高度的多样性，造成TCR的普适性较低，常规的TCR则存在这样的问题：
按照传统技术对人的外周血T细胞进行测序(成本较低)，可测得十万、百万级数量的α及β链序列，但是无法确定哪些是来自于同一个细胞，且无法确定正确配对的α-β对；而采用更先进的单细胞测序技术，可得到正确配对的α-β对，可经化学合成之后再进行功能筛选，但因α、β肽链长合成成本高、进行筛选数量多、耗时长，导致针对某一疾病靶点开发免疫治疗的难度非常大。
发明内容
基于此，有必要针对上述问题，提供一种靶向HCMV的TCR，可通过T细胞过继性免疫治疗，特异性识别、杀死病人体内的HCMV病毒，并建立长期的免疫记忆。
一种靶向HCMV的TCR，所述TCR包括α链的CDR1、CDR2和CDR3可变域，以及β链的CDR1、CDR2和CDR3可变域，所述α链的CDR3可变域选自SEQ ID NO:1序列，所述β链的CDR3可变域选自SEQ ID NO:2序列。
上述靶向HCMV的TCR，包括α链(CDR1，CDR2，CDR3)的以及β链(CDR1，CDR2，CDR3)，其中，α链的CDR3和β链的CDR3区选自特定的序列，通过上述序列的正确配对，可实现对HCMV的亲和靶向；从而可将包括上述TCR的T细胞通过体外扩增并回输到病人体内，由于该T细胞能够特异性识别HCMV病毒抗原，从而重构病人对HCMV病毒的免疫功能，抑制病毒增殖并杀死被感染细胞。
在其中一个实施例中，所述α链可变域的CDR1、CDR2可变域分别选自SEQ ID NO:3序列、SEQ ID NO:4序列；所述β链可变域的CDR1、CDR2可变域分别选自SEQ ID NO:5序列、SEQ ID NO:6序列。
上述正确配对的α链和β链，具有生物活性，能够起到特异性识别HCMV病毒，建立长期免疫记忆的功效。
可以理解的，所述靶向HCMV的TCR，除上述可变域外，其余序列可通过查阅公开数据库如IMGT(http://www.imgt.org/)、VDJdb(https://vdjdb.cdr3.net/search)等来获得人的恒定区氨基酸序列，结合上述的CDR3β、CDR3α序列信息，即可得到整条TCR的氨基酸序列。
在其中一个实施例中，所述TCR序列如SEQ ID NO:8所示。
在其中一个实施例中，所述TCRα链的CDR1、CDR2和CDR3可变域与SEQ ID NO:3序列、SEQ ID NO:4序列和SEQ ID NO:1序列具有90％以上的相似性；所述TCRβ链的CDR1、CDR2和CDR3可变域与SEQ ID NO:5序列、SEQ ID NO:6序列和SEQ ID NO:2序列具有90％以上的相似性。
本发明还公开了上述的靶向HCMV的TCR的获得方法，包括以下步骤：
1)从外周血中分离得到原代CD8+ T细胞，与搭载CMV抗原多肽的抗原呈递细胞共孵育，靶向CMV的原代CD8+ T细胞受刺激后增殖，达到富集效果；
2)针对上述靶向CMV的CD8+ T细胞，制备TCR表达文库和测序文库，经高通量测序得到TCR文库所有TCR序列信息以及TCR的富集情况；
3)将TCR表达文库导入细菌体内涂板筛选得到阳性单克隆菌落，经测序，将序列与高通量测序结果进行比对，根据上述TCR的富集情况，挑选得到富集的TCR，获得其序列信息；
4)在细胞水平验证上述获得TCR的功能，获得靶向HCMV的阳性TCR。
上述方法中，通过将CD8+ T细胞，与搭载CMV抗原多肽的抗原呈递细胞(DC细胞)共孵育，后者可刺激靶向CMV的CD8+ T细胞的增殖，以达到富集效果，而出现富集情况(即数量增多)的TCR才有可能是阳性的TCR。可以理解的，针对靶向CMV的CD8+ T细胞克隆得TCR文库的方法，按照常规方法即可，如可参考WO2020036875A1文献公开方法。在步骤3)中，因靶向CMV的TCR经富集之后，占TCR文库的大多数，随机挑选细菌单克隆即可容易获得靶向CMV的TCR(不止一个)，随后再将测序结果与高通量测序结果比对，属于被富集的序列，为目标阳性TCR。
在其中一个实施例中，步骤1)中，所述CMV抗原多肽为SEQ ID NO:7所示序列。
在其中一个实施例中，步骤1)中，所述抗原呈递细胞与所述CD8+ T细胞的数量比为1:3-5。
在其中一个实施例中，步骤3)中，将所述阳性TCR的核酸序列克隆至pJET1.2质粒，再将质粒文库导入工程菌内，经菌液涂板并培养，得到阳性单克隆菌落；经测序，与步骤2)中得到的TCR序列信息进行比对，得到阳性单克隆菌落的TCR序列信息。
在其中一个实施例中，步骤4)中，在细胞水平验证上述获得TCR的功能；具体采用以下方法：通过CMV-Tetramer PE染色，鉴定所述TCR是否正确识别并结合CMV-Tetramer，如可正确识别并结合CMV-Tetramer，即为靶向HCMV的阳性TCR。可以理解的，也可以采用其他能够确认TCR是否能够正确靶向目标的方法，仅需确认TCR为目标阳性TCR即可。
本发明还公开了一种靶向HCMV的T细胞，表达上述的靶向HCMV的TCR。
本发明还公开了一种上述的靶向HCMV的TCR在制备用于治疗和预防HCMV感染疾病药物中的应用。
本发明还公开了一种上述的靶向HCMV的TCR在制备用于检测HCMV的诊断试剂中的应用。
本发明还公开了一种用于HCMV感染疾病药物，包括上述的靶向HCMV的TCR。
与现有技术相比，本发明具有以下有益效果：
本发明的一种靶向HCMV的TCR，通过反复试验和验证后筛选得到，该TCR包括α链(CDR1，CDR2，CDR3)的以及β链(CDR1，CDR2，CDR3)，能够特异性识别HCMV病毒抗原，可将包括上述TCR的T细胞通过体外扩增并回输到病人体内，从而重构病人对HCMV病毒的免疫功能，抑制病毒增殖并杀死被感染细胞。
附图说明
图1为实施例1中流式细胞术检测靶向CMV的CD8+ T细胞含量结果图；
图2为实施例2中流式细胞术检测表达本TCR的T细胞与CMV结合的结果图；
图3为实施例3中流式细胞术检测表达TCR0的T细胞与CMV结合的结果图；
图4为本TCR与TCR0结合CMV效果对比图。
具体实施方式
为了便于理解本发明，下面将参照相关附图对本发明进行更全面的描述。附图中给出了本发明的较佳实施例。但是，本发明可以以许多不同的形式来实现，并不限于本文所描述的实施例。相反地，提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。
以下实施例所用试剂除特别说明外，均为市售可得。
实施例1
一种靶向HCMV的TCR，通过以下方法获得：
1、制备靶向CMV的CD8+ T细胞。
1.1细胞复苏。
1)取出一管外周血细胞，37℃水浴孵育至刚好完全溶解；
2)将解冻后的外周血细胞转移至新的50mL离心管，用5min时间缓慢加入4mL 20％FBS RPMI-1640，室温静置10min后，20℃800rpm离心8min，弃去上清液；
3)用2mL基础培养基(X-Vivo 15培养基+1％P/S双抗)重悬细胞并计数(数量为8.5×106个/mL)，再加入1mL基础培养基，调整细胞密度为5.6×106个/mL(注：用基础培养基调整细胞密度至5-10×106个/mL即可)。
1.2外周血细胞贴壁并培养。
1)取6孔板，向两个孔分别加入1.5mL上述细胞悬液，37℃、5％CO2培养3小时；
注：按1×106个/cm2加入相应体积的细胞悬液，6孔板的面积约9.6cm2；
2)弃去液体，用1mL枪头添加37℃预热的X-Vivo 15培养基，冲洗培养板两次。冲洗时应使培养基充分接触培养孔的每一处，并轻柔吹打培养基，使未贴壁细胞被重复冲洗下来，弃去液体；
3)向培养孔中各加入3mL完全培养基(含8％v/v HI-FBS、800IU/mL GM-CSF及500U/mL IL-4)刺激分化，37℃、5％CO2培养48小时；
4)添加1.5mL新鲜的完全培养基(含2400IU/mL GM-CSF及1500U/mL IL-4)，37℃、5％CO2培养24小时。
1.3多肽及细胞因子刺激DC细胞分化成熟。
1)收集未成熟的DC细胞(抗原呈递细胞)：上述培养板每孔吸取1.5mL上清液后，用力吹打剩余的培养基使细胞从孔壁上剥落下来，如有需要，可用冷的X-Vivo15培养基再次冲洗培养板。收集细胞悬液，显微镜下观察并计数。
2)用含细胞因子的培养基重悬：离心上述细胞悬液，弃去上清后，用1mL预热的完全培养基(含8％v/v HI-FBS、800IU/mL的GM-CSF、500U/mL的IL-4、10ng/mL的LPS及100IU/mL的IFN-γ)重悬并计数(1.8×106个/mL×1mL＝1.8×106个)，再加入1mL上述完全培养基；
3)不添加多肽的对照：取上述细胞悬液400μL(约含3.6×105个DC细胞)，加入200μL上述培养基后，转移至24孔板中的一个孔内；
4)多肽刺激：向步骤2)的细胞悬液补加0.4mL完全培养基(含8％体积浓度的HI-FBS、800IU/mL的GM-CSF、500U/mL的IL-4、10ng/mL的LPS及100IU/mL的IFN-γ)，添加2μL浓度为10mg/mL的CMV多肽(生工合成，序列为NLVPMVATV(SEQ ID NO:7)，以下简写为“pep”)至终浓度10μg/mL，接种至6孔板的一个孔内；
5)步骤3)、步骤4)的细胞悬液37℃、5％CO2培养16小时；
6)丝裂霉素C(MMC)溶液制备：用0.33mL DMSO(浓度为15mg/mL)溶解5mg MMC，按14μL/管分装。将MMC溶液加入细胞培养液之前，应用培养基或水进一步稀释，确保MMC被充分溶解。MMC溶液应避免重复冻融；
7)向步骤5)的细胞悬液中分别加入丝裂霉素C至100μg/mL，37℃、5％CO2孵育30min。
1.4收集DC细胞。
1)先收集培养孔中的培养基，再用wash buffer(不含Ca2+及Mg2+的PBS)用力冲洗培养孔壁，将DC细胞冲洗下来；
2)将上述两份溶液混合，并添加wash buffer补足体积至8mL，20℃800rpm离心8min收集细胞，并用2mL wash buffer重悬；
3)向步骤1)的培养孔中添加冷的wash buffer，冰上孵育20min后，用wash buffer将孔壁上的DC细胞冲洗下来，并与步骤2)的溶液混合；
3)20℃800rpm离心8min收集细胞，用含10％HI-FBS的X-Vivo 15培养基重悬，使细胞浓度为5×105个/mL。
1.4分离CD8+ T细胞
1)重复1.1的步骤1)、2)、3)；
2)取6孔板，向两个孔分别加入1.5mL上述细胞悬液，37℃、5％CO2培养16小时，收集未贴壁的细胞悬液；
3)用1mL枪头添加37℃预热的X-Vivo 15培养基，冲洗培养板两次。冲洗时应使培养基充分接触培养孔的每一处，并轻柔吹打培养基，重悬未贴壁细胞后收集起来，与步骤2)的未贴壁细胞悬液合并处理；
注：通过试剂盒(EasySepTM Human CD8+ T Cell Enrichment Kit,StemCell,19053)分离CD8+T细胞，其含量通常为84-95％，根据操作的不同而有所不同，以下为详细步骤：
4)收集上述步骤的细胞于15mL离心管，20℃800rpm离心8min；
5)弃去上清液，用2mL PBS重悬细胞并计数(3.77×106个/mL×2mL＝7.54×106个)；
6)离心弃去上清液，加入300μL推荐的培养基重悬细胞；
7)将上述细胞悬液转移至5mL(12×75mm)聚苯乙烯圆底管，按50μL/mL的浓度加入试剂盒组分Cocktail(即加入15μL Cocktail)，混匀后室温孵育10min；
8)震荡磁珠溶液30s，使磁珠充分打散。按150μL/mL的浓度将磁珠加至上述细胞悬液中(即加入45μL磁珠)，混匀后室温孵育5min；
9)添加推荐的培养基至总体积为2.5mL。用枪头轻轻吹打2-3次混匀。
10)将聚苯乙烯圆底管(不含盖子)置于磁力架上，室温孵育5min；
11)磁珠充分被磁力架吸附固定住后，将细胞悬液倒至新的管，并计数(9.15×105个/mL×2.3mL＝2.1×106个)；
12)20℃800rpm离心8min，弃去上清液，用X-Vivo 15培养基(含10％HI-FBS、60ng/mL IL-21)重悬细胞，使其最终的细胞浓度为2×106个/mL。
1.6DC细胞和T细胞共培养
1)混合1.4收集的DC细胞200μL、1.5收集的T细胞200μL(1：1的体积比)，则DC细胞：T细胞的数量比为1：4，转移至48孔板培养。设置的对照培养组如下：
表1.DC细胞和T细胞共培养设计
| 组别 | DC细胞 | T细胞 | 备注 |
| well.1 | 200μL(不含抗原多肽pep) | 200μL | 阴性对照 |
| well.2 | 200μL(含抗原多肽pep) | 200μL | 设置若干个平行孔 |
2)传代培养：37℃、5％CO2培养72小时后，用预热至37℃的X-Vivo 15培养基(含10％HI-FBS，5ng/mL IL-15及5ng/mL IL-7)补足每孔体积至400μL，转移至已加入400μL上述培养基的24孔板培养；
3)37℃、5％CO2再培养72小时后，细胞计数如下：
表2.细胞计数情况一
| 组别 | 细胞密度 | 体积/μL | 细胞数 |
| well.1 | 6.75×10<sup>5</sup>cells/mL | 700 | 4.73×10<sup>5</sup> |
| well.2 | 8.8×10<sup>5</sup>cells/mL | 700 | 6.16×10<sup>5</sup> |
4)传代培养：添加适当体积预热至37℃的X-Vivo 15培养基(含10％HI-FBS，5ng/mL IL-15及5ng/mL IL-7)补足每孔体积至800μL，转移至已加入800μL上述培养基的12孔板培养；
5)37℃、5％CO2再培养48小时后，细胞计数如下：
表3.细胞计数情况二
| 组别 | 细胞密度 | 体积/mL | 细胞数 |
| well.1 | 6.8×10<sup>5</sup>cells/mL | 1.4 | 9.52×10<sup>5</sup> |
| well.2 | 1.82×10<sup>6</sup>cells/mL | 1.4 | 2.52×10<sup>6</sup> |
6)传代培养：添加适当体积预热至37℃的X-Vivo 15培养基(含10％HI-FBS，5ng/mL IL-15及5ng/mL IL-7)补足每孔体积至1.6mL，转移至已加入1.6mL上述培养基的6孔板培养，37℃、5％CO2培养48小时。
1.7流式细胞术检测靶向CMV的CD8+ T细胞含量
1)取样并计数：
表4.细胞计数情况三
| 组别 | 细胞密度 | 体积/μL | 细胞数 |
| well.1 | 3.0×10<sup>5</sup>cells/mL | 800 | 2.4×10<sup>5</sup> |
| well.2 | 6.25×10<sup>5</sup>cells/mL | 400 | 2.5×10<sup>5</sup> |
2)所有样本用1mL冷的PBS冲洗一次后，用80μL wash buffer重悬并转移至1.5mLEP管。每个样品染色方案如下，与染料混合后4℃孵育15-20min；
表5.染色方案
3)加入1.4mL wash buffer，4℃800rpm离心8min，弃去上清液，用300μL washbuffer重悬细胞，上机(美国Beckman cytoflex S流式细胞分析仪)分析，分析结果如图1所示；
4)设门方法：先用"Lymphocytes"设门，圈出T细胞群，如图1-A所示，图中线圈框中部分为T细胞群，占73.91％；然后用"single cells"设门，去除粘连细胞，如图1-B所示，图中线圈框中部分为目标细胞群，单细胞占64.02％；再用"DAPI-"设门，圈出活细胞，如图1-C所示，图中线框圈中部分为活细胞，占97.37％；最后，如图1-D所示，在图1-D右上角CD8及CMV双阳性区域的细胞，即为靶向CMV的CD8+ T细胞，占68.88％。
2、克隆得到TCR文库并进行高通量测序。
参照常规技术，如WO 2020036875A1文献公开方法，针对上述目标细胞，克隆得到TCR表达文库并进行高通量测序。高通量测序的数据经分析，可得知被富集的TCR序列，这些被富集的TCR具有较大概率为目标TCR。
3、获取阳性TCR序列信息。
采用常规分子克隆技术，将TCRs克隆到pJET1.2质粒(商业质粒，携带的筛选标记物为黄色荧光蛋白YFP)上，再将质粒文库导入大肠杆菌工程菌内，经菌液涂板并培养，得到阳性单克隆菌落。因靶向CMV的TCR经富集之后，数量达到TCR总数的近70％，随机挑选细菌单克隆容易获得目标TCR，经一代测序，将测序结果与高通量测序结果比对，同时属于阳性单克隆菌落及被富集的序列，为目标TCR的序列信息，该TCR的序列如SEQ ID NO:8所示，其中α链和β链的CDR1、CDR2和CDR3可变域如下表所示。
表6.TCR序列
实施例2
实施例1获得的TCR，出现于经pep刺激后进行了大量增殖的细胞，有较大的概率为目标TCR。
本实施例通过CMV-Tetramer PE染色，鉴定表达实施例1获得的TCR的T细胞能否正确识别并结合CMV，以验证其功能。
1、构建表达TCR的细胞系
1)所用细胞系为Jurkat细胞(敲除TCR并永久表达CD8α和CD8β，即JB4细胞)。取5×106个细胞，转移至15mL离心管，20℃800rpm离心8min收集细胞，用2mL PBS重悬后计数；
2)取1×106个细胞，20℃800rpm离心8min收集细胞，用50μL Buffer R(试剂盒组分)重悬；
3)准备24孔板，向两个孔内分别加入500μL RPMI1640培养基(含10％FBS，不含抗生素)，并放置于37℃培养箱内预热。
4)取上述Buffer R重悬的细胞悬液10μL，与800ng pJET1.2-TCR质粒轻柔混合，按NeonTM电转系统的标准操作进行电转，设置的电转条件为：1600V电压，放电10ms，脉冲3次；
5)每个样本经电转后，迅速转移至步骤3)所述的24孔板的一个培养孔内，轻轻晃动培养板，确保细胞充分分散；
6)于37℃、5％CO2培养48小时，即为JB4-TCR细胞。
2、流式细胞术检测阳性细胞量
1)细胞表面标记物及ICS染色：取3×105个细胞于1.5mL离心管，加入1mL冷的PBS洗涤一次，用80μL wash buffer重悬。染色步骤如下：
用CMV-Tetramer PE于4℃染色45min，再加入DAPI、YFP于4℃染色15min。然后加入1.4mL wash buffer，4℃800rpm离心8min收集细胞，用300μL wash buffer重悬。
2)上机分析，实验结果如图2所示，(Q1-UR+Q1-LR)区域为成功表达TCR的T细胞，Q1-UR区域为表达了正确识别并结合CMV-Tetramer的T细胞，即89.7％(Q1-UR/(Q1-UR+Q1-LR))的表达TCR的T细胞能够正确识别并结合CMV-Tetramer，证明了本TCR正确识别并结合CMV的功能。
实施例3
本实施例将本发明得到的TCR与TCR0(已报道的TCR)进行性能对比。
其中，已报道TCR0序列如SEQ ID NO:9所示。
参照实施例2所述的方法，实验结果如图3所示。表达TCR0的T细胞(以下简称“对照组”，表达本TCR的T细胞以下简称“实验组”)，仅有33.9％(Q1-UR/(Q1-UR+Q1-LR))能够与CMV-Tetramer结合，与图2的89.7％差别明显。
进一步地，对两次实验的细胞数量进行均一化处理，调整细胞数量一致，结果如图4所示：实验组的阴性样本(TRC YFP-NEG，细胞数为1812)与对照组的阴性样本(TRC0YFP-NEG，细胞数为1845)，对CMV-Tetramer的响应信号基本一致，而实验组的阳性样本(TRCYFP-POS，细胞数为1996)对CMV-Tetramer的响应信号明显强于对照组的阳性样本(TRC0YFP-POS，细胞数为1997)，即峰形明显右移，可知本发明的TCR对CMV的响应效果优于已报道的TCR0。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
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Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His Phe
210 215 220
Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp Thr
225 230 235 240
Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala Trp
245 250 255
Gly Arg Ala Asp Cys Gly Phe Thr Ser Val Ser Tyr Gln Gln Gly Val
260 265 270
Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu
275 280 285
Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys Arg
290 295 300
Lys Asp Phe Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser
305 310 315 320
Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala
325 330 335
Ser Ala Pro Ile Ser Met Leu Ala Met Leu Phe Thr Leu Ser Gly Leu
340 345 350
Arg Ala Gln Ser Val Ala Gln Pro Glu Asp Gln Val Asn Val Ala Glu
355 360 365
Gly Asn Pro Leu Thr Val Lys Cys Thr Tyr Ser Val Ser Gly Asn Pro
370 375 380
Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Asn Arg Gly Leu Gln Phe Leu
385 390 395 400
Leu Lys Tyr Ile Thr Gly Asp Asn Leu Val Lys Gly Ser Tyr Gly Phe
405 410 415
Glu Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Lys Lys Pro
420 425 430
Ser Ala Leu Val Ser Asp Ser Ala Leu Tyr Phe Cys Ala Val Arg Asp
435 440 445
Thr Asn Ala Arg Leu Met Phe Gly Asp Gly Thr Gln Leu Val Val Lys
450 455 460
Pro Asn Ile Gln Asn Pro Asp Pro
465 470
<210> 9
<211> 606
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Met Gly Ile Arg Leu Leu Cys Arg Val Ala Phe Cys Phe Leu Ala Val
1 5 10 15
Gly Leu Val Asp Val Lys Val Thr Gln Ser Ser Arg Tyr Leu Val Lys
20 25 30
Arg Thr Gly Glu Lys Val Phe Leu Glu Cys Val Gln Asp Met Asp His
35 40 45
Glu Asn Met Phe Trp Tyr Arg Gln Asp Pro Gly Leu Gly Leu Arg Leu
50 55 60
Ile Tyr Phe Ser Tyr Asp Val Lys Met Lys Glu Lys Gly Asp Ile Pro
65 70 75 80
Glu Gly Tyr Ser Val Ser Arg Glu Lys Lys Glu Arg Phe Ser Leu Ile
85 90 95
Leu Glu Ser Ala Ser Thr Asn Gln Thr Ser Met Tyr Leu Cys Ala Ser
100 105 110
Ser Phe Gln Gly Tyr Thr Glu Ala Phe Phe Gly Gln Gly Thr Arg Leu
115 120 125
Thr Val Val Glu Asp Leu Asn Lys Val Phe Pro Pro Glu Val Ala Val
130 135 140
Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Thr Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln
180 185 190
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser
195 200 205
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His
210 215 220
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
225 230 235 240
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
245 250 255
Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Val Ser Tyr Gln Gln Gly
260 265 270
Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr
275 280 285
Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys
290 295 300
Arg Lys Asp Phe Arg Ala Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe
305 310 315 320
Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met
325 330 335
Ala Ser Ala Pro Ile Ser Met Leu Ala Met Leu Phe Thr Leu Ser Gly
340 345 350
Leu Arg Ala Gln Ser Val Ala Gln Pro Glu Asp Gln Val Asn Val Ala
355 360 365
Glu Gly Asn Pro Leu Thr Val Lys Cys Thr Tyr Ser Val Ser Gly Asn
370 375 380
Pro Tyr Leu Phe Trp Tyr Val Gln Tyr Pro Asn Arg Gly Leu Gln Phe
385 390 395 400
Leu Leu Lys Tyr Ile Thr Gly Asp Asn Leu Val Lys Gly Ser Tyr Gly
405 410 415
Phe Glu Ala Glu Phe Asn Lys Ser Gln Thr Ser Phe His Leu Lys Lys
420 425 430
Pro Ser Ala Leu Val Ser Asp Ser Ala Leu Tyr Phe Cys Ala Asp Tyr
435 440 445
Tyr Gly Gln Asn Phe Val Phe Gly Pro Gly Thr Arg Leu Ser Val Leu
450 455 460
Pro Tyr Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser
465 470 475 480
Lys Ser Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln
485 490 495
Thr Asn Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys
500 505 510
Thr Val Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val
515 520 525
Ala Trp Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn
530 535 540
Ser Ile Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys
545 550 555 560
Asp Val Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn
565 570 575
Phe Gln Asn Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val
580 585 590
Ala Gly Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
595 600 605
Claims (4)
1.一种靶向HCMV的TCR，其特征在于，所述TCR包括α链的CDR1、CDR2和CDR3可变域，以及β链的CDR1、CDR2和CDR3可变域，所述α链的CDR1、CDR2、CDR3可变域分别选自：SEQ ID NO:3序列、SEQ ID NO:4序列、SEQ ID NO:1序列，所述β链的CDR1、CDR2、CDR3可变域分别选自SEQID NO:5序列、SEQ ID NO:6序列、SEQ ID NO:2序列。
2.根据权利要求1所述的靶向HCMV的TCR，其特征在于，所述TCR序列如SEQ ID NO:8所示。
3.一种靶向HCMV的T细胞，其特征在于：表达权利要求1-2任一项所述的靶向HCMV的TCR。
4.权利要求1-2任一项所述的靶向HCMV的TCR在制备用于检测HCMV的诊断试剂中的应用。
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