Carcinoembryonic antigen-related cellular adhesion molecule 1 isoforms alternatively inhibit and costimulate human T cell function
Carcinoembryonic antigen-related cellular adhesion molecule 1 isoforms alternatively inhibit and costimulate human T cell function
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DOI：
10.4049/jimmunol.172.6.3535
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发表时间：
2004-03-15
影响因子：
4.4
通讯作者：
Blumberg, RS
中科院分区：
文献类型：
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作者：
Chen, DH;Iijima, H;Blumberg, RS
癌胚抗原相关细胞粘附分子1（CEACAM 1）是一组跨膜蛋白亚型，由不同数量的细胞外Ig样结构域以及含有两个基于免疫受体酪氨酸的抑制基序的长胞质（cyt）尾或独特的短胞质尾组成。尽管据报道CEACAM 1在激活后在T淋巴细胞表面表达，但由于缺乏每个CEACAM 1亚型的功能特征，其在T细胞调节中的作用存在争议。因此，我们共转染Jurkat T细胞与CEACAM 1亚型编码结构和IL-2启动子携带质粒或小干扰RNA靶向src同源结构域2含有磷酸酶1。在荧光素酶报告基因测定中，并通过测量细胞因子分泌（IL-2、IL-4和IFN-γ），含有长或短cyt尾的CEACAM 1分别抑制或共刺激TCR/CD 3复合物加CD 28介导的活化，其中长cyt尾的抑制功能占主导地位。CEACAM 1的抑制功能依赖于含有磷酸酶1活性的src同源结构域2，需要细胞质尾的免疫受体酪氨酸抑制基序结构域内的两个酪氨酸残基，并通过促分裂原活化蛋白激酶途径介导。CEACAM 1介导的抑制可通过分别在同种异体刺激或促有丝分裂刺激存在下将PBMC与CEACAM 1特异性mAb或CEACAM 1-Fc融合蛋白孵育来功能性重建。这些研究表明，CEACAM 1的长和短细胞尾分别在T细胞调节中充当抑制性和共刺激性受体。
Carcinoembryonic Ag-related cellular adhesion molecule 1 (CEACAM1) represents a group of transmembrane protein isoforms that consist of variable numbers of extracellular Ig-like domains together with either a long cytoplasmic (cyt) tail containing two immunoreceptor tyrosine-based inhibitory motifs or a unique short cyt tail. Although CEACAM1 has been reported to be expressed on the surface of T lymphocytes upon activation, its roles in T cell regulation are controversial due to the lack of functional characterization of each individual CEACAM1 isoform. We thus cotransfected Jurkat T cells with CEACAM1 isoform-encoding constructs and an IL-2 promoter-bearing plasmid or a small interference RNA targeting src homology domain 2 containing phosphatase 1. In a luciferase reporter assay and through measurements of cytokine secretion (IL-2, IL-4, and IFN-gamma), CEACAM1 containing either a long or a short cyt tail inhibited or, costimulated, respectively, TCR/CD3 complex plus CD28 mediated activation with the inhibitory functions of the long cyt tail dominating. The inhibitory function of CEACAM1, was dependent upon src homology domain 2 containing phosphatase 1 activity, required both tyrosine residues within the immunoreceptor tyrosine-based inhibitory motif domains of the cyt tail and was mediated through the mitogen-activated protein kinase pathway. CEACAM1-mediated inhibition could be functionally reconstituted by incubation of PBMC with either a CEACAM1-specific mAb or CEACAM1-Fc fusion protein in the presence of an allogeneic or mitogenic stimulus, respectively. These studies indicate that the long and short cyt tails of CEACAM1 serve as inhibitory and costimulatory receptors, respectively, in T cell regulation.