2012-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/654969摘要：在各種不同的免疫反應中,輔助T細胞常扮演著保護性或破壞性的雙重角色。因此在許多治療免疫相關疾病的臨床試驗中，即是採取調節輔助T細胞的分化及功能為策略。目前在許多疾病的治療裡,迫切需要更能專一性地針對不同輔助T細胞的方法來達到更好的療效。然而在發展此種專一性的療法，更需要對於T細胞的發育及功能有全面性的了解與認識。先前的研究指出：c-Maf(一種leucine-zipper類的轉錄因子)在輔助T細胞的分化中扮演很重要的角色。C-Maf會藉由TCR活化刺激的ICOS訊號開始產生。它主要表現在第二型(Th2)、第十七型(Th17)、調節性第一型(Tr1)以及濾泡性輔助T細胞(Tfh)中。在Th2細胞中，c-Maf專一地調控介白素四(IL-4)基因的表現，藉此促進分化成Th2細胞。而在Th17、Tr1及Tfh細胞中，c-Maf主要在調控介白素二十一(IL-21)基因的表現，進一步幫助這些輔助T細胞的增殖與分化。此外c-Maf還會調控輔助T細胞的增生和細胞凋亡。轉錄因子的活性調控常常藉由磷酸化來達成。本實驗室初步的研究發現：c-Maf 轉錄因子在活化的輔助T細胞中，其tyrosine residues會被磷酸化，而c-Maf轉錄因子的活性會被tyrosine 磷酸化所調節。我們計畫研究c-Maf的tyrosine residues在磷酸化之後的免疫功能變化。而在了解c-Maf 的磷酸化機制之後，將有助於釐清如何調節相關輔助T細胞的功能，以期能發展出針對治療免疫相關疾病的專一性T細胞療法。<br> Abstract: Helper T (Th) cells play a crucial role in both protective and destructive immune responses. Modulating the differentiation and function of T cells can be beneficial in many clinical settings. There is an urgent need for more of T cell-specific therapeutics to treat a variety of diseases. The development of such reagents requires in-depth understanding of the molecular mechanisms regulating the development and function of T cells. Published data have demonstrated that c-Maf, a leucine-zipper transcription factor, plays a very important role in Th cells. It is induced by ICOS signals and preferentially expressed in Th2, Th17, Tfh (follicular helper T), Tr1, but not Th1 cells. C-Maf is a potent and specific transactivator of the IL-4 gene, thereby promoting the differentiation of Th2 cells. Moreover, c-Maf directly transactivates IL-21 gene and is critical for the expansion and differentiation of Th17, Tfh and Tr1 cells. In addition, c-Maf can modulate the proliferation and apoptosis of Th cells. Phosphorylation modulates protein function in response to different signals. Our preliminary data indicate that c-Maf is phosphorylated at tyroinse residues in activated Th cells and that the activity of c-Maf is critically regulated by tyrosine phosphorylation in a gene-dependent manner. Here, we propose to investigate the functional consequence of tyrosine phosphorylation of c-Maf in this study. Importantly, understanding the regulatory mechanism of c-Maf tyrosine phosphorylation will allow us to modulate the activity of c-Maf and develop novel T cell-specific therapeutics for immune-related diseases.磷酸化c-Maf輔助T細胞Tyrosine Phosphorylationc-MafTh2 cellsTh17 cells and Tfh Cells