IL-15对HIV疫苗免疫效应的影响及HIV感染者TCR Vδ1 CDR3肽及其识别的抗原表位肽的筛选与鉴定
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摘要
自从上个世纪80年代人类免疫缺陷病毒(human immunodeficiency virus, HIV)被发现以来,感染HIV所致的获得性免疫缺陷综合征,简称艾滋病(acquired immune deficiency syndrome, AIDS)在全球迅速传播,现已成为一种严重危害人类健康的疾病,对HIV/AIDS的预防、诊断、治疗也因此成为医学工作者的首要任务之一。研制安全有效的HIV疫苗是预防HIV感染的重要措施之一,研究者们一直致力于如何激发机体产生足够强度的细胞免疫和体液免疫并加强免疫记忆。本课题组前期研究显示,IL-15在抗肿瘤免疫中具有增强免疫反应的作用,且小鼠实验证实IL-15质粒能够增强HIV gag疫苗的免疫效应,同时能促进中枢记忆性T细胞分化及增强长期记忆性免疫应答。因此,本研究的第一部分将观察以痘苗病毒天坛株为载体的重组IL-15在小鼠体内对重组HIV gag痘苗病毒载体疫苗免疫效应的影响,以及在灵长类动物体内IL-15质粒对HIV疫苗免疫效应的影响,以进一步探索IL-15作为HIV疫苗佐剂的前景。
在以痘苗病毒天坛株为载体的研究中,将IL-15基因编码片段插入至复制型痘苗病毒载体,体外检测了IL-15蛋白的表达及表达上清中IL-15的生物活性。将重组IL-15痘苗病毒与重组HIV gag痘苗病毒共同免疫小鼠后,酶联免疫斑点法(enzyme-linked immunospot assay, ELI SPOT)测定结果显示,在痘苗病毒的高剂量组和低剂量组,IL-15共免疫均未能增加小鼠体内抗HIV gag抗原特异性IFN-γ分泌的CD8+T淋巴细胞频率,反而使其降低；同时IL-15对HIV特异性体液免疫也无增强作用。
在灵长类动物研究中,本研究以IL-15重组质粒与HIV多价的DNA疫苗共同免疫恒河猴,然后用重组HIV痘苗病毒疫苗进行加强免疫。结果显示,IL-15重组质粒与HIV DNA疫苗共同免疫后,恒河猴体内的HIV特异性的T细胞反应与HIV疫苗单独免疫无明显差异,体液免疫在两组间也无明显差异。在HIV痘苗病毒疫苗加强免疫后,IL-15重组质粒共免疫的恒河猴的HIV特异性T细胞反应比HIV疫苗单独免疫组稍强,而且前者的抗HIV env蛋白抗体滴度明显高于后者。流式细胞术检测显示,在几乎所有的检测时间点,IL-15重组质粒共免疫组的动物外周血中记忆性CD8+T细胞的比例明显高于HIV疫苗单独免疫组,提示IL-15能够诱导更多的效应性T细胞向记忆性T细胞转化。
综上所述,重组IL-15天坛株痘苗病毒对HIV gag痘苗病毒疫苗无免疫增强作用,反而减弱其免疫效应,故IL-15可能不适合用于天坛株痘苗病毒载体疫苗体系；在灵长类动物实验中,IL-15能够增加恒河猴外周血中记忆性T细胞的比例,同时还可以增强长期的体液免疫反应,提示IL-15可以增强HIV疫苗的长期免疫反应。
本文的第二部分为HIV感染者TCR Vδ1 CDR3肽及其识别的抗原表位肽的筛选与鉴定,研究的对象是HIV感染者体内的γδT细胞。γδT细胞作为连接固有性免疫和特异性免疫的桥梁,虽然其在外周血T细胞中所占的比例仅为1-10%,但是在抗感染过程中发挥着重要的作用。业已证明,在HIV感染者外周血中γδT细胞在绝对数量上有4-5倍的扩增,且主要是Vδ1亚型,而Vγ9/δ2γδT细胞却处于免疫无能状态。这种改变的具体机制目前仍不清楚。本实验室主要从事γδT细胞研究,证实了TCRδ链的CDR3区是γδT细胞与抗原结合的关键部位,本研究从以上理论出发,进行了如下实验：
首先分离9例HIV感染者外周血单个核细胞,经反转录聚合酶链式反应(reverse transcription-polymerase chain reaction, RT-PCR)扩增γδTCR Vδ1区基因,将扩增片段重组到pGEM-T载体上进行测序,结果获得了两条优势的CDR3肽：CALGVTTALIQWGFVYTDKLIF (HP1)和CALGEPPIYFNWGIRVTDKPIF (HP2)。
然后利用得到的两条优势的CDR3肽(HP1和HP2)为探针,筛选噬菌体随机十二肽库。通过非特异性洗脱和特异性洗脱两种方法,我们得到了3条优势十二肽：WHWQWTPWSIQP、WHWNAWNWSSQQ和WHWSWIQNAAPN,这3条十二肽的共有序列为WHW。合成以上3条十二肽,进行初步的生物学分析：通过酶联免疫吸附法(enzyme-linked immunosorbent assay, ELISA)和流式细胞术(flow cytometry, FCM),在分子和细胞水平验证十二肽与探针和γδTCR的结合；利用固相扩增的方法,通过流式细胞术和二甲基偶氮唑蓝(3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide, MTT)法验证合成的十二肽对γδT细胞群体的促增殖作用。
以上结果显示,本研究得到了HIV感染者外周血中TCRδ1链的优势CDR3肽的序列,并利用优势的CDR3δ肽通过筛选噬菌体随机十二肽库得到了Vδ1 T细胞识别的候选抗原表位肽,为研究HIV病程中Vδ1 T细胞的作用提供了新思路。
Since human immunodeficiency virus (HIV) was identified as the pathogen of acquire immune deficiency syndrome (AIDS) in the 1980's, great efforts have been made to fight against this virus rampant on the earth. An effective vaccine is in urgent need for preventing or treating HIV infections worldwide. Throughout the research and development of HIV vaccines, researchers have focused on promoting cellular and humoral immune response, and maintaining the memory immune response. At our lab, IL-15 has been demonstrated to promote antitumor immune response by enhancing the CTL and NK cell activities. Then IL-15 plasmid was shown to enhance the HIV gag DNA vaccine induced cellular and humoral immune response, promote differentiation of memory CD8+T cells precursors into central memory T cells, and maintain the long-term memory immune response in mice. In this study, the effects of recombinant IL-15 for HIV vaccine both in vaccinia virus Tiantan strain vectors in mice, and the effects of plasmid IL-15 for multivalent HIV DNA vaccine in primates were further evaluated.
In the study using vaccinia virus Tiantan strain as the vector, human IL-15 cDNA was inserted into the replicative vaccinia virus vector, and then the expression of IL-15 and the bioactivity of IL-15 in supernatant of in vitro culture were investigated. Mice were co-immunized with recombinant IL-15 vaccinia virus and recombinant HIV gag vaccinia virus, and the HIV gag specific cellular immune response was detected by IFN-y secreting ELISPOT analysis. The ELISPOT analysis indicated that IL-15 did not promote the frequency of HIV gag specific IFN-y secreting CD8+T cells in mice neither in high dose group nor in low dose group, but rather made the frequency of HIV specific CD8+T cells lower. Also, recombinant IL-15 vaccinia virus coadministration did not bring any benefit to the humoral immune response.
In the study in primates, rhesus monkeys were co-immunized with IL-15 plasmid and HIV multivalent DNA vaccine; then recombinant HIV vaccinia virus vaccine was used for boosting immunization. After three times of DNA immunization, there was no significant difference between the group of co-immunized with IL-15/HIV DNA vaccine and the group immunized with HIV DNA vaccine alone in terms of HIV specific cellular and humoral immune response. After boosting with the recombinant HIV Tiantan strain vaccinia virus (rTV), the number of IFN-y spot forming cells per million PBMC was higher in IL-15 coadministrated monkeys than that of HIV vaccine immunized alone monkeys; furthermore, the titer of anti-HIV Env antibody was significantly higher in IL-15 co-immunized group than that in the group without IL-15. Also, flow cytometric analysis indicated that the percentage of CD8+memory T cells in peripheral blood was significantly higher in IL-15 co-immunization group than that in HIV vaccine immunized group at almost all the time points detected, which suggested that IL-15 could promote the turnover of effector T cells into memory T cells.
Taken together, recombinant IL-15 Tiantan strain vaccinia virus did not augment the immune response induced by recombinant HIV gag vaccinia virus, but made it weaker, suggesting that IL-15 might not be an ideal adjuvant for the Tiantan strain vaccinia virus system. However, in rhesus monkeys, IL-15 plasmid coadministration increased the percentage of memory T cells in the peripheral blood, and augmented the long-lasting humoral immune response, which suggested that IL-15 could enhance the long-time immune response of HIV vaccine.
The second part of the study is about screening and identification of the CDR3 of TCR V81 in HIV-infected patients along with corresponding antigen epitope peptides.γδT cells, only 1-10% of T lymphocytes in peripheral blood, are the linkage of the innate immunity and the adaptive immunity, and play an important role in anti-tumor and anti-infection immunity. It has been reported that the absolute number ofγδT cells in the peripheral blood of HIV infected patients were 4-5 fold higher than that in healthy controls, and most of theγδT cells in HIV patients were 81 in subtype, which is only 5-10% ofγδT cells in healthy people. On the contrary, Vy9/82γδT cells as the major subtype ofγδT cells in normal were decreased in number and generally anergic during anti-HIV immune response. The mechanism of these changes has not been clarified so far. Our lab focuses on the study ofγδT cells, and has proved that the CDR3 in the TCRδchain is the vital region during the antigen recognition ofγδTCR. Based on the above-mentioned studies, my study included:
First, PBMCs from 9 HIV infected patients were collected and the cDNA of Vδ1γδTCR were amplified by RT-PCR, and then the cDNA of Vδ1 was connected into pGEM-T vector and sequenced. Two dominant sequences of CDR3δ, CALGVTTALIQ WGFVYTDKLIF(named HP1) and CALGEPPIYFNWGIRVTDKPIF(named HP2) were obtained.
Secondly, two CDR38 peptides, HP1 and HP2, were used as probes to screen the Ph.D.-12TM Phage Display Peptide Library. Three dominant 12-mers peptides with a common motif of WHW:WHWQWTPWSIQP, WHWNAWNWSSQQ and WHWSWIQNAAPN, were obtained after non-specific elution and specific elution. Then the three 12-mers peptides were synthesized and their biological functions were observed in vitro. The binding of synthesized peptides andγδTCR was identified by ELISA (enzyme-linked immunosorbent assay) and flow cytometry at molecular and cellular levels. Furthermore, the synthesized peptides could stimulate the proliferation ofγδT cells in solid-phase expansion assay by flow cytometry and MTT anaylsis.
In brief, two dominant CDR3 sequences of TCR81 in peripheral blood of HIV infected patients, and theγδ1 T cell recognized candidate epitope peptides by screening the Ph.D.-12TM Phage Display Peptide Library using the dominant CDR3δas probes were obtained, which support a new research model for the effect of Vδ1 T cells in HIV infections.
在以痘苗病毒天坛株为载体的研究中,将IL-15基因编码片段插入至复制型痘苗病毒载体,体外检测了IL-15蛋白的表达及表达上清中IL-15的生物活性。将重组IL-15痘苗病毒与重组HIV gag痘苗病毒共同免疫小鼠后,酶联免疫斑点法(enzyme-linked immunospot assay, ELI SPOT)测定结果显示,在痘苗病毒的高剂量组和低剂量组,IL-15共免疫均未能增加小鼠体内抗HIV gag抗原特异性IFN-γ分泌的CD8+T淋巴细胞频率,反而使其降低；同时IL-15对HIV特异性体液免疫也无增强作用。
在灵长类动物研究中,本研究以IL-15重组质粒与HIV多价的DNA疫苗共同免疫恒河猴,然后用重组HIV痘苗病毒疫苗进行加强免疫。结果显示,IL-15重组质粒与HIV DNA疫苗共同免疫后,恒河猴体内的HIV特异性的T细胞反应与HIV疫苗单独免疫无明显差异,体液免疫在两组间也无明显差异。在HIV痘苗病毒疫苗加强免疫后,IL-15重组质粒共免疫的恒河猴的HIV特异性T细胞反应比HIV疫苗单独免疫组稍强,而且前者的抗HIV env蛋白抗体滴度明显高于后者。流式细胞术检测显示,在几乎所有的检测时间点,IL-15重组质粒共免疫组的动物外周血中记忆性CD8+T细胞的比例明显高于HIV疫苗单独免疫组,提示IL-15能够诱导更多的效应性T细胞向记忆性T细胞转化。
综上所述,重组IL-15天坛株痘苗病毒对HIV gag痘苗病毒疫苗无免疫增强作用,反而减弱其免疫效应,故IL-15可能不适合用于天坛株痘苗病毒载体疫苗体系；在灵长类动物实验中,IL-15能够增加恒河猴外周血中记忆性T细胞的比例,同时还可以增强长期的体液免疫反应,提示IL-15可以增强HIV疫苗的长期免疫反应。
本文的第二部分为HIV感染者TCR Vδ1 CDR3肽及其识别的抗原表位肽的筛选与鉴定,研究的对象是HIV感染者体内的γδT细胞。γδT细胞作为连接固有性免疫和特异性免疫的桥梁,虽然其在外周血T细胞中所占的比例仅为1-10%,但是在抗感染过程中发挥着重要的作用。业已证明,在HIV感染者外周血中γδT细胞在绝对数量上有4-5倍的扩增,且主要是Vδ1亚型,而Vγ9/δ2γδT细胞却处于免疫无能状态。这种改变的具体机制目前仍不清楚。本实验室主要从事γδT细胞研究,证实了TCRδ链的CDR3区是γδT细胞与抗原结合的关键部位,本研究从以上理论出发,进行了如下实验：
首先分离9例HIV感染者外周血单个核细胞,经反转录聚合酶链式反应(reverse transcription-polymerase chain reaction, RT-PCR)扩增γδTCR Vδ1区基因,将扩增片段重组到pGEM-T载体上进行测序,结果获得了两条优势的CDR3肽：CALGVTTALIQWGFVYTDKLIF (HP1)和CALGEPPIYFNWGIRVTDKPIF (HP2)。
然后利用得到的两条优势的CDR3肽(HP1和HP2)为探针,筛选噬菌体随机十二肽库。通过非特异性洗脱和特异性洗脱两种方法,我们得到了3条优势十二肽：WHWQWTPWSIQP、WHWNAWNWSSQQ和WHWSWIQNAAPN,这3条十二肽的共有序列为WHW。合成以上3条十二肽,进行初步的生物学分析：通过酶联免疫吸附法(enzyme-linked immunosorbent assay, ELISA)和流式细胞术(flow cytometry, FCM),在分子和细胞水平验证十二肽与探针和γδTCR的结合；利用固相扩增的方法,通过流式细胞术和二甲基偶氮唑蓝(3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide, MTT)法验证合成的十二肽对γδT细胞群体的促增殖作用。
以上结果显示,本研究得到了HIV感染者外周血中TCRδ1链的优势CDR3肽的序列,并利用优势的CDR3δ肽通过筛选噬菌体随机十二肽库得到了Vδ1 T细胞识别的候选抗原表位肽,为研究HIV病程中Vδ1 T细胞的作用提供了新思路。
Since human immunodeficiency virus (HIV) was identified as the pathogen of acquire immune deficiency syndrome (AIDS) in the 1980's, great efforts have been made to fight against this virus rampant on the earth. An effective vaccine is in urgent need for preventing or treating HIV infections worldwide. Throughout the research and development of HIV vaccines, researchers have focused on promoting cellular and humoral immune response, and maintaining the memory immune response. At our lab, IL-15 has been demonstrated to promote antitumor immune response by enhancing the CTL and NK cell activities. Then IL-15 plasmid was shown to enhance the HIV gag DNA vaccine induced cellular and humoral immune response, promote differentiation of memory CD8+T cells precursors into central memory T cells, and maintain the long-term memory immune response in mice. In this study, the effects of recombinant IL-15 for HIV vaccine both in vaccinia virus Tiantan strain vectors in mice, and the effects of plasmid IL-15 for multivalent HIV DNA vaccine in primates were further evaluated.
In the study using vaccinia virus Tiantan strain as the vector, human IL-15 cDNA was inserted into the replicative vaccinia virus vector, and then the expression of IL-15 and the bioactivity of IL-15 in supernatant of in vitro culture were investigated. Mice were co-immunized with recombinant IL-15 vaccinia virus and recombinant HIV gag vaccinia virus, and the HIV gag specific cellular immune response was detected by IFN-y secreting ELISPOT analysis. The ELISPOT analysis indicated that IL-15 did not promote the frequency of HIV gag specific IFN-y secreting CD8+T cells in mice neither in high dose group nor in low dose group, but rather made the frequency of HIV specific CD8+T cells lower. Also, recombinant IL-15 vaccinia virus coadministration did not bring any benefit to the humoral immune response.
In the study in primates, rhesus monkeys were co-immunized with IL-15 plasmid and HIV multivalent DNA vaccine; then recombinant HIV vaccinia virus vaccine was used for boosting immunization. After three times of DNA immunization, there was no significant difference between the group of co-immunized with IL-15/HIV DNA vaccine and the group immunized with HIV DNA vaccine alone in terms of HIV specific cellular and humoral immune response. After boosting with the recombinant HIV Tiantan strain vaccinia virus (rTV), the number of IFN-y spot forming cells per million PBMC was higher in IL-15 coadministrated monkeys than that of HIV vaccine immunized alone monkeys; furthermore, the titer of anti-HIV Env antibody was significantly higher in IL-15 co-immunized group than that in the group without IL-15. Also, flow cytometric analysis indicated that the percentage of CD8+memory T cells in peripheral blood was significantly higher in IL-15 co-immunization group than that in HIV vaccine immunized group at almost all the time points detected, which suggested that IL-15 could promote the turnover of effector T cells into memory T cells.
Taken together, recombinant IL-15 Tiantan strain vaccinia virus did not augment the immune response induced by recombinant HIV gag vaccinia virus, but made it weaker, suggesting that IL-15 might not be an ideal adjuvant for the Tiantan strain vaccinia virus system. However, in rhesus monkeys, IL-15 plasmid coadministration increased the percentage of memory T cells in the peripheral blood, and augmented the long-lasting humoral immune response, which suggested that IL-15 could enhance the long-time immune response of HIV vaccine.
The second part of the study is about screening and identification of the CDR3 of TCR V81 in HIV-infected patients along with corresponding antigen epitope peptides.γδT cells, only 1-10% of T lymphocytes in peripheral blood, are the linkage of the innate immunity and the adaptive immunity, and play an important role in anti-tumor and anti-infection immunity. It has been reported that the absolute number ofγδT cells in the peripheral blood of HIV infected patients were 4-5 fold higher than that in healthy controls, and most of theγδT cells in HIV patients were 81 in subtype, which is only 5-10% ofγδT cells in healthy people. On the contrary, Vy9/82γδT cells as the major subtype ofγδT cells in normal were decreased in number and generally anergic during anti-HIV immune response. The mechanism of these changes has not been clarified so far. Our lab focuses on the study ofγδT cells, and has proved that the CDR3 in the TCRδchain is the vital region during the antigen recognition ofγδTCR. Based on the above-mentioned studies, my study included:
First, PBMCs from 9 HIV infected patients were collected and the cDNA of Vδ1γδTCR were amplified by RT-PCR, and then the cDNA of Vδ1 was connected into pGEM-T vector and sequenced. Two dominant sequences of CDR3δ, CALGVTTALIQ WGFVYTDKLIF(named HP1) and CALGEPPIYFNWGIRVTDKPIF(named HP2) were obtained.
Secondly, two CDR38 peptides, HP1 and HP2, were used as probes to screen the Ph.D.-12TM Phage Display Peptide Library. Three dominant 12-mers peptides with a common motif of WHW:WHWQWTPWSIQP, WHWNAWNWSSQQ and WHWSWIQNAAPN, were obtained after non-specific elution and specific elution. Then the three 12-mers peptides were synthesized and their biological functions were observed in vitro. The binding of synthesized peptides andγδTCR was identified by ELISA (enzyme-linked immunosorbent assay) and flow cytometry at molecular and cellular levels. Furthermore, the synthesized peptides could stimulate the proliferation ofγδT cells in solid-phase expansion assay by flow cytometry and MTT anaylsis.
In brief, two dominant CDR3 sequences of TCR81 in peripheral blood of HIV infected patients, and theγδ1 T cell recognized candidate epitope peptides by screening the Ph.D.-12TM Phage Display Peptide Library using the dominant CDR3δas probes were obtained, which support a new research model for the effect of Vδ1 T cells in HIV infections.
引文
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