CD226及其配体CD112/CD155分子相互作用机制的研究
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摘要
血小板/T细胞活化抗原1(platelet and T cell activation antigen 1, PTA1)属于免疫球蛋白超家族(immunoglobulin superfamily, IgSF)成员,其胞膜外区含有2个V样结构域。在2000年召开的第七届人类白细胞分化抗原国际协作组会议(HLDA7)上获得编号CD226。CD226分子最早通过单克隆抗体(monoclonal antibody,mAb)LeoA1被发现,在使用人混合淋巴细胞反应(mixed lymphocyte reaction,MLR)得到的活化细胞免疫小鼠时获得LeoA1,它所识别的抗原称为T细胞谱系特异的活化抗原1(T lineage-specific activation antigen 1, TLiSA1)。随后发现除活化T细胞表达外,该分子也分布于血小板,因而命名为血小板/T细胞活化抗原1。美国DNAX研究所也研究了同一蛋白分子,并命名其为DNAM-1(DNAX accessory molecue-1)。该分子于1996年基因克隆成功,cDNA全长2603bp,包含7个外显子,开放读框编码336个氨基酸,胞浆区具有磷酸化及与信号分子相互作用的位点。CD226分子与表达于杀伤性T细胞(CTL)和NK细胞的CD96(Tactile)分子在蛋白水平有22%的同源性,与BGP-1、CD36、PRR和果蝇神经胶质蛋白Neuroglian也有一定的同源性。CD226基因产物是分子量约为65kDa的I型跨膜糖蛋白,表达于T细胞、NK细胞、NKT细胞、单核细胞、巨核/血小板谱系及活化的血管内皮细胞;广泛参与了免疫系统的生理和病理学功能,如T细胞、巨核细胞的分化,NK细胞对肿瘤细胞、病毒感染细胞的杀伤,血小板的活化与聚集,单核/巨噬细胞穿越血管内皮细胞等过程,并参与其中的信号转导。
CD226分子体内天然配体于2003年得到鉴定,为同属于nectin/Necl家族的黏附分子:人脊髓灰质炎病毒受体(PVR/Necl-5/CD155)及其家族成员人PVR受体相关分子(PRR-2/nectin-2/CD112),CD112同时也是单纯疱疹病毒(HSV-1和HSV-2)的受体。CD226的配体表达广泛,包括神经细胞、上皮细胞、内皮细胞和成纤维细胞等。在与CD112和CD155相互作用后,CD226分子可以向细胞内传递活化型信号,参与固有免疫和适应性免疫应答,引发多种免疫学效应,包括细胞间的黏附、浸润及杀伤活性的发挥等过程。但是目前有关这些细胞间黏附分子相互作用的确切分子机制尚不完全清楚。CD226、CD112和CD155分子同属于免疫球蛋白超家族成员,胞膜外区具有相似的空间结构,这一类黏附分子是通过什么样的结构域相互作用从而传递了活化性的信号仍不明确。探讨参与CD226与其配体CD112和CD155分子作用的蛋白结构域,有助于深入理解黏附分子、杀伤细胞活化型受体等免疫细胞膜分子激活的分子机制。
本研究首先通过RT-PCR方法,从人结肠癌细胞系SW480中克隆出CD226分子的两种配体CD112和CD155基因的开放读框全长。针对其胞膜外区(extracellular domain,ED)基因序列和相应的目的载体多克隆位点,合成带有酶切位点的引物,将CD112和CD155分子胞膜外区分别插入可以表达分泌型融合蛋白(带有人IgG Fc段标签)的真核表达载体pCMD7,转染CHO细胞并在真核细胞抗生素G-418选择压力下培养和有限稀释法克隆化筛选后,分别获得了可稳定表达CD112ED-Fc和CD155ED-Fc融合蛋白(C端带有Fc标签)的CHO细胞株,用抗Fc单抗亲和层析柱纯化融合蛋白,并利用纯化的融合蛋白免疫BALB/c小鼠,各制备了一套可满足免疫印迹、免疫沉淀、免疫组化染色、流式细胞术以及功能实验要求的单克隆抗体,并利用该单抗初步分析了CD112和CD155分子在机体免疫系统抗肿瘤中的作用,以及CD155分子在正常和肿瘤组织中的表达。
由于现有真核表达载体pCMD7的多克隆位点过于简单,所以我们改构了pSecTag2B载体,使其可以表达带有3C酶识别位点和C端Fc标签的融合蛋白。利用该载体,同上述方案分别建立了可以稳定分泌胞膜外区第一个和第二个结构域的CD226D1-Fc和CD226D2-Fc融合蛋白的CHO细胞株。纯化的融合蛋白可用于细胞杀伤、细胞黏附等免疫学功能实验模型,以分析CD226分子与其配体CD112/CD155分子相互作用的结构域。
应用可溶型分子液相与固相结合试验,发现CD112或CD155与固相化全长CD226分子有较高的结合能力,而与CD226D1和D2的结合能力明显下降。采用CFSE/PI双标记法以及NK细胞为效应细胞、K562细胞为靶细胞的杀伤实验中,CD226-Fc以及CD112-Fc和CD155-Fc融合蛋白均可以明显抑制NK细胞的杀伤活性,而CD226D1-Fc和CD226D2-Fc的抑制作用很弱;FMU-CD112.8和FMU-CD155.12 mAb也具有抑制作用。说明CD226-CD112和CD226-CD155相互作用都参与了NK细胞识别和杀伤靶细胞。采用CFSE荧光标记的PBMC与ECV304内皮细胞黏附阻断实验模型证实,CD226全长分子可以显著抑制PBMC与ECV304细胞之间的黏附,同样发现CD226D1和CD226D2的抑制作用非常弱。
本实验研究中,我们还构建了含CD226胞膜外区不同结构域的截短体和CD226/ICAM-1绿色荧光蛋白嵌合体分子,及其配体CD112/CD155分子与红色荧光蛋白融合表达载体,转染CHO细胞后,采用激光扫描共聚焦显微镜(laser scanning confocal microscope, LSCM)观察分析了CD226与其配体CD112和CD155分子间的相互作用结构域。结果显示,单独CD226第1结构域(羧基端连接ICAM-I分子胞膜外区第5结构域和跨膜区、胞浆区)或者单独CD226第2结构域(氨基端连接ICAM-I分子胞膜外区第1结构域)的嵌合体膜型分子均不能与细胞表面膜型CD112或CD155分子有效结合,只有包括了D1和D2的完整CD226分子才能有效结合CD112或CD155分子,并引发相应分子在细胞膜上的极化和聚集,出现明显的帽形成(capping)。
上述多个模型的实验均证实,CD226分子胞膜外区2个V样结构域都参与了同配体的结合;在高浓度可溶形式条件下,CD226分子胞膜外区单独一个结构域仍可以与配体分子以较低的亲和力结合,可以部分的模拟天然分子的结合效应,但胞膜外区2个V样结构域的完整性对于CD226与其配体有效结合及活化信号的传递是必需的,缺失任何一个结构域都不能有效的与相应配体发生高亲和力的结合,也不能诱导受体和配体膜分子在相应细胞膜表面的极化和聚集。说明CD226与配体的结合有赖于完整的蛋白空间构象。这些实验结果为进一步深入研究免疫细胞活化型受体CD226分子参与机体多种免疫学功能的分子机制奠定了实验基础。
Human platelet and T cell activation antigen 1 (PTA1) is a member of the immunoglobulin superfamily (IgSF) containing 2 Ig-V like domains in its extracellular region. It was designated as CD226 in the 7th Workshop and Conference on Human Leukocyte Differentiation Antigen (HLDA7) in 2000. In 1985, T lineage-specific activation antigen 1 (TLiSA1) was first discovered by a mAb LeoA1 which was prepared by immunizing mice with MLR generated activated lymphocytes. It was subsequently found TLiSA1 was involved in platelet activation and aggregation, hence renamed PTA1. In 1996, human CD226 was cloned by DNAX Research Institute designated as DNAM-1 (DNAX accessory molecule-1). The full length of CD226 cDNA has 2603bp, and its ORF encoding 336 amino acids is composed of 7 exons. There are some phosphorylation sites in its cytoplasmic region. At protein level, CD226 shows 22% homology with CD96 (Tactile) which is expressed on activated T cells and NK cells, and also shares certain homology to BGP-1, CD36, PRR, and drosophila nerve colloid protein-Neuroglian. CD226 is a 65kDaⅠtype transmembrane glycoprotein expressed on cell surface of T cells, NK cells, NKT cells, monocytes/macrophages, megakaryocytes and platelets, and activated vascular endothelial cells, which is involved in a variety of immunological functions, including the differentiation of T cells and megakaryocytes, the cytotoxicity of NK cells against tumor cells and virus infected cells, the activation and aggregation of platelets, and the transmigration of monocytes/macrophages through vascular endothelial cells.
In 2003, human poliovirus receptor (PVR/Necl-5/CD155) and its nectin/Necl (nectin-like) family member poliovirus receptor related 2 (PRR-2/ nectin-2/CD112) were identified as the ligands for CD226. CD112 also serves as the receptor for herpes simplex virus (HSV-1 and HSV-2). The CD226 ligands are expressed on many kinds of cells such as neuronal, epithelial, endothelial and fibroblastic cells. Interaction of CD226 with its ligands CD112 and CD155 induces intercellular adhesion, infiltration and cell signaling, participating in both innate and adaptive immunities. Until now however, the precise interaction mechanism between CD226 and its ligands is not fully understood. Although CD226, CD112 and CD155 share the similar three-dimensional structure, it is still unclear which domain(s) are involved in the activation and signal tranduction in this adhesion molecule. To explore the interaction of CD226 domain(s) with its ligands can help us to understand the function mechaniam of CD226 such as adhesion and cytotoxicity.
At first, we cloned the full length of CD112 and CD155 from human colon cancer cell line SW480 by RT-PCR respectively. Primers were designed and synthesized according to the extracellular domain (ED) of CD112 and CD155 and the restriction enzyme sites in the vector. In order to obtain soluble Fc fusion protein, the ED of CD112 or CD155 was cloned into eukaryotic expression vector pCMD7 respectively, and the constructs were transfected into CHO cells. After G418 selection and limited dilution cloning, CHO cell lines which can stably secrete CD112ED-Fc and CD155ED-Fc (Fc tag in C-terminal) fusion protein were obtained, then the proteins were purified from the supernatants of the CHO cell culture by anti-Fc affinity chromatography column. Hybridomas secreting monoclonal antibodies (mAbs) to CD112 and CD155 were obtained via immunizing BALB/c mice with the purified fusion proteins and routine hybridoma technique. These mAbs can be used in the experiments of western blot, immunoprecipitation, immunohistochemistry (IHC), immunofluorescent staining, as well as functional study. Using these mAbs we investigated the expression pattern of CD155 in normal and tumor tissues, and the roles of CD112 or CD155 in anti-tumor immune responses.
Furthermore, in order to overcome the shortcoming that the pCMD7 vector only has limited multiple cloning sites (MCS), pSecTag2B vector was reconstructed to express the fusion protein which contains 3C enzyme recognision site and C-terminal Fc tag. Using this vector, we obtained the CHO cell lines which can stably express CD226D1-Fc and CD226D2-Fc fusion proteins, with the human Fc tag at C terminal of the first or the second domain of CD226 extracellular region respectively. We analyzed the interaction domain(s) of CD226 and its ligands CD112 and CD155 with these fusion proteins. Moreover, the domain(s) of CD226 molecule participating in the NK cells killing to tumor cells and human PBMC adhesion to endothelial cells were identified.
Using the model of soluble fusion proteins binding to coated CD226 molecule, we found that full length CD226 have much stronger ability to bind CD112 and CD155, while CD226D1 and D2 truncates only have low binding ability. In the flow-cytometric NK-cytotoxicity assay using CFSE/PI labeling, the presence of fusion protein CD226-Fc, CD112-Fc and CD155-Fc could inhibit the NK killing against K562 target cells obviously, and FMU-CD112.8 and FMU-CD155.12 mAbs could inhibit this killing activity to some extent, whereas CD226D1-Fc and CD226D2-Fc did not show any inhibitory effect on the cytotoxicity. These results demonstrated that the interactions of CD226-CD112 and CD226-CD155 both participate in the process of NK cell recognizing and killing target cells. In the experiment of fluorescein labeling PBMC adhere to endothelial cell line ECV304, we found the presence of full length CD226 could inhibit the adhesion between PBMC and ECV304 markedly, while CD226D1 and CD226D2 almost could not inhibit the adhesion.
Finally, we constructed different vectors used for observation and analysis of the interaction by laser scanning confocal microscope (LSCM), which included all kinds of truncates of CD226 ED, chimeras of CD226/ICAM-1 fused to GFP, and CD112 or CD155 fused to RFP. We found that the chimeras which only have the first domain of CD226 (C-terminal linked to the fifth domain, transmembrane domain and cytoplamic region of ICAM-1) or the second domain of CD226 (N-terminal linked to the first domain of ICAM-1) could not bind CD112 or CD155 on the cell membrane effectively. Whereas the full length molecule containing CD226 D1 and D2 domains binded CD112 or CD155 effectively, and triggering polarization, aggregation, and capping of the receptor and its ligands were observed.
In conclusion, the integrity of two Ig-V like domains of CD226 in extracellular region is necessary for its binding to its ligands which further mediated cell-cell adhesion, signal transduction and NK cell cytotoxicity. These results lay an important foundation for the further exploration of the molecular mechanism of activating receptor CD226 in the multiple immune responses.
CD226分子体内天然配体于2003年得到鉴定,为同属于nectin/Necl家族的黏附分子:人脊髓灰质炎病毒受体(PVR/Necl-5/CD155)及其家族成员人PVR受体相关分子(PRR-2/nectin-2/CD112),CD112同时也是单纯疱疹病毒(HSV-1和HSV-2)的受体。CD226的配体表达广泛,包括神经细胞、上皮细胞、内皮细胞和成纤维细胞等。在与CD112和CD155相互作用后,CD226分子可以向细胞内传递活化型信号,参与固有免疫和适应性免疫应答,引发多种免疫学效应,包括细胞间的黏附、浸润及杀伤活性的发挥等过程。但是目前有关这些细胞间黏附分子相互作用的确切分子机制尚不完全清楚。CD226、CD112和CD155分子同属于免疫球蛋白超家族成员,胞膜外区具有相似的空间结构,这一类黏附分子是通过什么样的结构域相互作用从而传递了活化性的信号仍不明确。探讨参与CD226与其配体CD112和CD155分子作用的蛋白结构域,有助于深入理解黏附分子、杀伤细胞活化型受体等免疫细胞膜分子激活的分子机制。
本研究首先通过RT-PCR方法,从人结肠癌细胞系SW480中克隆出CD226分子的两种配体CD112和CD155基因的开放读框全长。针对其胞膜外区(extracellular domain,ED)基因序列和相应的目的载体多克隆位点,合成带有酶切位点的引物,将CD112和CD155分子胞膜外区分别插入可以表达分泌型融合蛋白(带有人IgG Fc段标签)的真核表达载体pCMD7,转染CHO细胞并在真核细胞抗生素G-418选择压力下培养和有限稀释法克隆化筛选后,分别获得了可稳定表达CD112ED-Fc和CD155ED-Fc融合蛋白(C端带有Fc标签)的CHO细胞株,用抗Fc单抗亲和层析柱纯化融合蛋白,并利用纯化的融合蛋白免疫BALB/c小鼠,各制备了一套可满足免疫印迹、免疫沉淀、免疫组化染色、流式细胞术以及功能实验要求的单克隆抗体,并利用该单抗初步分析了CD112和CD155分子在机体免疫系统抗肿瘤中的作用,以及CD155分子在正常和肿瘤组织中的表达。
由于现有真核表达载体pCMD7的多克隆位点过于简单,所以我们改构了pSecTag2B载体,使其可以表达带有3C酶识别位点和C端Fc标签的融合蛋白。利用该载体,同上述方案分别建立了可以稳定分泌胞膜外区第一个和第二个结构域的CD226D1-Fc和CD226D2-Fc融合蛋白的CHO细胞株。纯化的融合蛋白可用于细胞杀伤、细胞黏附等免疫学功能实验模型,以分析CD226分子与其配体CD112/CD155分子相互作用的结构域。
应用可溶型分子液相与固相结合试验,发现CD112或CD155与固相化全长CD226分子有较高的结合能力,而与CD226D1和D2的结合能力明显下降。采用CFSE/PI双标记法以及NK细胞为效应细胞、K562细胞为靶细胞的杀伤实验中,CD226-Fc以及CD112-Fc和CD155-Fc融合蛋白均可以明显抑制NK细胞的杀伤活性,而CD226D1-Fc和CD226D2-Fc的抑制作用很弱;FMU-CD112.8和FMU-CD155.12 mAb也具有抑制作用。说明CD226-CD112和CD226-CD155相互作用都参与了NK细胞识别和杀伤靶细胞。采用CFSE荧光标记的PBMC与ECV304内皮细胞黏附阻断实验模型证实,CD226全长分子可以显著抑制PBMC与ECV304细胞之间的黏附,同样发现CD226D1和CD226D2的抑制作用非常弱。
本实验研究中,我们还构建了含CD226胞膜外区不同结构域的截短体和CD226/ICAM-1绿色荧光蛋白嵌合体分子,及其配体CD112/CD155分子与红色荧光蛋白融合表达载体,转染CHO细胞后,采用激光扫描共聚焦显微镜(laser scanning confocal microscope, LSCM)观察分析了CD226与其配体CD112和CD155分子间的相互作用结构域。结果显示,单独CD226第1结构域(羧基端连接ICAM-I分子胞膜外区第5结构域和跨膜区、胞浆区)或者单独CD226第2结构域(氨基端连接ICAM-I分子胞膜外区第1结构域)的嵌合体膜型分子均不能与细胞表面膜型CD112或CD155分子有效结合,只有包括了D1和D2的完整CD226分子才能有效结合CD112或CD155分子,并引发相应分子在细胞膜上的极化和聚集,出现明显的帽形成(capping)。
上述多个模型的实验均证实,CD226分子胞膜外区2个V样结构域都参与了同配体的结合;在高浓度可溶形式条件下,CD226分子胞膜外区单独一个结构域仍可以与配体分子以较低的亲和力结合,可以部分的模拟天然分子的结合效应,但胞膜外区2个V样结构域的完整性对于CD226与其配体有效结合及活化信号的传递是必需的,缺失任何一个结构域都不能有效的与相应配体发生高亲和力的结合,也不能诱导受体和配体膜分子在相应细胞膜表面的极化和聚集。说明CD226与配体的结合有赖于完整的蛋白空间构象。这些实验结果为进一步深入研究免疫细胞活化型受体CD226分子参与机体多种免疫学功能的分子机制奠定了实验基础。
Human platelet and T cell activation antigen 1 (PTA1) is a member of the immunoglobulin superfamily (IgSF) containing 2 Ig-V like domains in its extracellular region. It was designated as CD226 in the 7th Workshop and Conference on Human Leukocyte Differentiation Antigen (HLDA7) in 2000. In 1985, T lineage-specific activation antigen 1 (TLiSA1) was first discovered by a mAb LeoA1 which was prepared by immunizing mice with MLR generated activated lymphocytes. It was subsequently found TLiSA1 was involved in platelet activation and aggregation, hence renamed PTA1. In 1996, human CD226 was cloned by DNAX Research Institute designated as DNAM-1 (DNAX accessory molecule-1). The full length of CD226 cDNA has 2603bp, and its ORF encoding 336 amino acids is composed of 7 exons. There are some phosphorylation sites in its cytoplasmic region. At protein level, CD226 shows 22% homology with CD96 (Tactile) which is expressed on activated T cells and NK cells, and also shares certain homology to BGP-1, CD36, PRR, and drosophila nerve colloid protein-Neuroglian. CD226 is a 65kDaⅠtype transmembrane glycoprotein expressed on cell surface of T cells, NK cells, NKT cells, monocytes/macrophages, megakaryocytes and platelets, and activated vascular endothelial cells, which is involved in a variety of immunological functions, including the differentiation of T cells and megakaryocytes, the cytotoxicity of NK cells against tumor cells and virus infected cells, the activation and aggregation of platelets, and the transmigration of monocytes/macrophages through vascular endothelial cells.
In 2003, human poliovirus receptor (PVR/Necl-5/CD155) and its nectin/Necl (nectin-like) family member poliovirus receptor related 2 (PRR-2/ nectin-2/CD112) were identified as the ligands for CD226. CD112 also serves as the receptor for herpes simplex virus (HSV-1 and HSV-2). The CD226 ligands are expressed on many kinds of cells such as neuronal, epithelial, endothelial and fibroblastic cells. Interaction of CD226 with its ligands CD112 and CD155 induces intercellular adhesion, infiltration and cell signaling, participating in both innate and adaptive immunities. Until now however, the precise interaction mechanism between CD226 and its ligands is not fully understood. Although CD226, CD112 and CD155 share the similar three-dimensional structure, it is still unclear which domain(s) are involved in the activation and signal tranduction in this adhesion molecule. To explore the interaction of CD226 domain(s) with its ligands can help us to understand the function mechaniam of CD226 such as adhesion and cytotoxicity.
At first, we cloned the full length of CD112 and CD155 from human colon cancer cell line SW480 by RT-PCR respectively. Primers were designed and synthesized according to the extracellular domain (ED) of CD112 and CD155 and the restriction enzyme sites in the vector. In order to obtain soluble Fc fusion protein, the ED of CD112 or CD155 was cloned into eukaryotic expression vector pCMD7 respectively, and the constructs were transfected into CHO cells. After G418 selection and limited dilution cloning, CHO cell lines which can stably secrete CD112ED-Fc and CD155ED-Fc (Fc tag in C-terminal) fusion protein were obtained, then the proteins were purified from the supernatants of the CHO cell culture by anti-Fc affinity chromatography column. Hybridomas secreting monoclonal antibodies (mAbs) to CD112 and CD155 were obtained via immunizing BALB/c mice with the purified fusion proteins and routine hybridoma technique. These mAbs can be used in the experiments of western blot, immunoprecipitation, immunohistochemistry (IHC), immunofluorescent staining, as well as functional study. Using these mAbs we investigated the expression pattern of CD155 in normal and tumor tissues, and the roles of CD112 or CD155 in anti-tumor immune responses.
Furthermore, in order to overcome the shortcoming that the pCMD7 vector only has limited multiple cloning sites (MCS), pSecTag2B vector was reconstructed to express the fusion protein which contains 3C enzyme recognision site and C-terminal Fc tag. Using this vector, we obtained the CHO cell lines which can stably express CD226D1-Fc and CD226D2-Fc fusion proteins, with the human Fc tag at C terminal of the first or the second domain of CD226 extracellular region respectively. We analyzed the interaction domain(s) of CD226 and its ligands CD112 and CD155 with these fusion proteins. Moreover, the domain(s) of CD226 molecule participating in the NK cells killing to tumor cells and human PBMC adhesion to endothelial cells were identified.
Using the model of soluble fusion proteins binding to coated CD226 molecule, we found that full length CD226 have much stronger ability to bind CD112 and CD155, while CD226D1 and D2 truncates only have low binding ability. In the flow-cytometric NK-cytotoxicity assay using CFSE/PI labeling, the presence of fusion protein CD226-Fc, CD112-Fc and CD155-Fc could inhibit the NK killing against K562 target cells obviously, and FMU-CD112.8 and FMU-CD155.12 mAbs could inhibit this killing activity to some extent, whereas CD226D1-Fc and CD226D2-Fc did not show any inhibitory effect on the cytotoxicity. These results demonstrated that the interactions of CD226-CD112 and CD226-CD155 both participate in the process of NK cell recognizing and killing target cells. In the experiment of fluorescein labeling PBMC adhere to endothelial cell line ECV304, we found the presence of full length CD226 could inhibit the adhesion between PBMC and ECV304 markedly, while CD226D1 and CD226D2 almost could not inhibit the adhesion.
Finally, we constructed different vectors used for observation and analysis of the interaction by laser scanning confocal microscope (LSCM), which included all kinds of truncates of CD226 ED, chimeras of CD226/ICAM-1 fused to GFP, and CD112 or CD155 fused to RFP. We found that the chimeras which only have the first domain of CD226 (C-terminal linked to the fifth domain, transmembrane domain and cytoplamic region of ICAM-1) or the second domain of CD226 (N-terminal linked to the first domain of ICAM-1) could not bind CD112 or CD155 on the cell membrane effectively. Whereas the full length molecule containing CD226 D1 and D2 domains binded CD112 or CD155 effectively, and triggering polarization, aggregation, and capping of the receptor and its ligands were observed.
In conclusion, the integrity of two Ig-V like domains of CD226 in extracellular region is necessary for its binding to its ligands which further mediated cell-cell adhesion, signal transduction and NK cell cytotoxicity. These results lay an important foundation for the further exploration of the molecular mechanism of activating receptor CD226 in the multiple immune responses.
引文
1 http://www.hlda.org.
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2 Burns GF, T.T., Werkmeister JA, et al. (1985) Tlisa, a human T lineage-specific activation antigen involved in the differentiation of cytotoxic T lymphocytes and anomalous killer cells from their precursors. J Exp Med 161, 1063-1078
3 Jin B, S.J., Vadas MA, et al. (1989) TGF beta down-regulates TliSA1 expression and inhibits the differentiation of precursor lymphocytes into CTL and LAK cells. Immunology 66, 570-576
4 Shibuya A, C.D., Hannum C, Yssel H, Franz-Bacon K, McClanahan T, Kitamura T, Nicholl J, Sutherland GR, Lanier LL, Phillips JH. (1996) DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphochtes. Immunity 4 (6), 573-581
5 Sherrington PD, S.J., Jin BQ, et al. (1997) Tlisa(PTA1) activation antigen implicated in T cell differentiation and platelet activation is a member of the immunoglobulin superfamily exhibiting distinctive regulation of expression. J Biol Chem 272, 21735-21744
6 张新海, 李., 欧阳为明, 等. (2002) 小鼠 CD226(PTA1)的基因克隆及其异型. 中国免疫学杂志 18 (6), 371-375
7 Tian F, L.D., Xia H, et al. (1998) Isolating of cDNA encoding gibbon and monkey platelet and T cell activation antigen 1. In Proceeding of 10th International Congress of Immunology (Vol. 41) (Editore, M., ed.), pp. 349-353
8 Tian F, L.D., Xia H et al. (1999) Isolation of cDNAs encoding gibbon and monkey platelet and T cell activation antigen 1 (PTA1) DNA Sequence 10 (3), 155-161
9 金伯泉. (2000) 第七届人类白细胞分化抗原专题讨论会简介. 上海免疫学杂志 20 (5)
10 金伯泉. (2000) HLDA7 专题讨论会新增 CD 抗编号和抗原. 细胞和分子免疫学杂志 16 (5), 373-375
11 Blons H, L.O., Houllier AM, Carnot F, Brasnu D, Beaune P, Zucman-Rossi J, Laurent-Puig P. (2002) Delineation and candidate gene mutation screening of the 18q22 minimal region of deletion in head and neck squamous cell carcinoma. Oncogene. 21 (32), 5016-5023
12 http://www.ncbi.nlm.nih.gov.
13 Jian JL, Z.C., Xu ZW, Ouyang WM, Ma DC, Zhang Y, Chen LJ, Yang AG, Jin BQ. (2006) Identification and characterization of the CD226 gene promoter. J Biol Chem 281 (39), 28731-28736
14 Ralston KJ, H.S., Zhang X, et al. (2004) The LFA-1-associated molecule PTA-1 (CD226) on T cells forms a dynamic molecular complex with protein 4.1G and human discs large. J Biol Chem 279 (32), 33816-33828
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