Differential induction of plasma cells by isoforms of human TACI
Differential induction of plasma cells by isoforms of human TACI
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DOI：
10.1182/blood-2014-05-575845
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发表时间：
2015-03-12
期刊：
影响因子：
20.3
通讯作者：
Cunningham-Rundles, Charlotte
中科院分区：
文献类型：
--
作者：
Garcia-Carmona, Yolanda;Cols, Montserrat;Cunningham-Rundles, Charlotte
常见变异型免疫缺陷受试者可能存在跨膜激活剂钙调节剂和亲环素配体相互作用因子（TACI）突变。与鼠基因不同，人TACI经历选择性信使（m）RNA剪接以产生具有1或2个配体结合结构域的同种型。因为这两种亚型都存在于人B细胞中，我们比较了它们在转导的鼠B和人前B细胞中的功能。尽管用长TACI同种型转导的鼠细胞和前B细胞保留表面CD19和免疫球蛋白G，但用短TACI同种型转导的细胞完全丧失了这些B细胞特征。短TACI亚型的表达产生强烈的核因子κ B活化，核p65易位，并与髓样分化因子88和钙调节亲环素配体共定位。短TACI转导的细胞变得更大，CD138阳性，表现出上调BLIMP1和XBP1 mRNA，并获得浆细胞的形态。相反，携带长同种型的细胞具有显著较少的BLIMP1和XBP1 mRNA，并且对于人前B细胞，保持CD138阴性。虽然人B细胞表达两种亚型，但短亚型在CD 27（+）B细胞、toll样受体9激活的外周B细胞和脾边缘区B细胞中占优势。虽然异构体的选择性剪接的转录控制仍然未知，但通过异构体的差异信号可能控制人类浆细胞的产生。
Subjects with common variable immune deficiency may have mutations in transmembrane activator calcium modulator and cyclophilin ligand interactor (TACI). Unlike the murine gene, human TACI undergoes alternative messenger (m) RNA splicing to produce isoforms with 1 or 2 ligand-binding domains. Because both isoforms are found in human B cells, we compared their functions in transduced murine B and human pre-B cells. Although murine cells and pre-B cells transduced with the long TACI isoform retained surface CD19 and immunoglobulin G, cells transduced with the short TACI isoform completely lost these B-cell characteristics. Expression of the short TACI isoform produced intense nuclear factor kappa B activation, nuclear p65 translocation, and colocalization with myeloid differentiation factor 88 and calcium-modulating cyclophilin ligand. The short TACI-transduced cells became larger and CD138 positive, demonstrated upregulated BLIMP1 and XBP1 mRNA, and acquired the morphology of plasma cells. In contrast, cells bearing the long isoform had significantly less BLIMP1 and XBP1 mRNA and, for human pre-B cells, remained CD138 negative. Although human B cells express both isoforms, the short isoform predominates in CD27(+) B cells, toll-like receptor 9-activated peripheral B cells, and splenic marginal zone B cells. Although the transcriptional controls for alternative splicing of isoforms remain unknown, differential signals via isoforms may control plasma-cell generation in humans.