Extracellular Isoforms of CD6 generated by alternative splicing regulate targeting of CD6 to the immunological synapse
Extracellular Isoforms of CD6 generated by alternative splicing regulate targeting of CD6 to the immunological synapse
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DOI：
10.4049/jimmunol.178.7.4351
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发表时间：
2007-04-01
影响因子：
4.4
通讯作者：
Carmo, Alexandre M.
中科院分区：
文献类型：
--
作者：
Castro, Monica A. A.;Oliveira, Marta I.;Carmo, Alexandre M.
绝大多数哺乳动物基因产生多个转录本。差异mRNA加工，但在极少数情况下，替代形式被赋予不同的功能特性。我们已经克隆并表征了辅助分子CD 6的一种新的同种型，其缺乏CD 166结合结构域，并在大鼠和人的原代细胞中表达。新的同种型，CD 6 Delta d3，由外显子5跳跃产生，因此缺乏CD 6的第三个清道夫受体富含半胱氨酸（SRCR）结构域。SRCR结构域3的差异表达导致了显着的功能差异：而全长CD 6靶向免疫突触，CD 6Ad 3是无法本地化在T细胞：APC界面在Ag呈递。CD 6变体的表达分析表明，虽然与全长CD 6的共表达更频繁，但CD 6Ad 3同种型在小百分比的T细胞中构成唯一的物种。在大鼠胸腺中，CD 6Ad 3在双阳性胸腺细胞中较少，但在近50%的单阳性CD 4或CD 8胸腺细胞中可检测到，这表明全长和Delta d3亚型之间的CD 6转换可能参与胸腺选择。引人注目的是，CD 6 Delta d3在T淋巴细胞活化后显著上调，部分取代全长CD 6，如通过单细胞水平的RT-PCR分析、通过免疫印迹和通过使用识别人CD 6的SRCR结构域1和3的Ab的流式细胞术所评估的。这种控制CD 166结合结构域表达的优雅机制可能有助于调节CD 6通过不同类型的细胞外接合传递的信号传导。
The great majority of mammalian genes yield multiple transcripts arising from. differential mRNA processing, but in very few instances have alternative forms been assigned distinct functional properties. We have cloned and characterized a new isoform of the accessory molecule CD6 that lacks the CD166 binding domain and is expressed in rat and human primary cells. The novel isoform, CD6 Delta d3, results from exon 5 skipping and consequently lacks the third scavenger receptor cysteine-rich (SRCR) domain of CD6. Differential expression of the SRCR domain 3 resulted in a remarkable functional difference: whereas full-length CD6 targeted to the immunological synapse, CD6Ad3 was unable to localize at the T cell:APC interface during Ag presentation. Analysis of expression of CD6 variants showed that, while being more frequent in coexpression with full-length CD6, the CD6Ad3 isoform constituted the sole species in a small percentage of T cells. In the rat thymus, CD6Ad3 is less represented in double-positive thymocytes but is detectable in nearly 50% of single-positive CD4 or CD8 thymocytes, suggesting that CD6 switching between full-length and Delta d3 isoforms may be involved in thymic selection. Strikingly, CD6 Delta d3 is markedly up-regulated upon activation of T lymphocytes, partially substituting full-length CD6, as evaluated by RT-PCR analysis at the single-cell level, by immunoblotting, and by How cytometry using Abs recognizing SRCR domains 1 and 3 of human CD6. This elegant mechanism controlling the expression of the CD166 binding domain may help regulate signaling delivered by CD6, through different types of extracellular engagement.