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Title: | T細胞過度表現轉形生長因子-β或Foxp3對其調節功能的影響 Overexpression of TGF-β or Foxp3 in T Cells on Their Regulatory Function |
Authors: | Han-Fang Cheng 鄭涵方 |
Advisor: | 江伯倫(Bor-Luen Chiang) |
Keyword: | 調節性T細胞,轉型生長因子, regulatory T cells,Foxp3,TGF-beta, |
Publication Year : | 2006 |
Degree: | 碩士 |
Abstract: | 免疫系統能使人體免除外來的病原體的威脅。後天免疫系統能分辨自體抗原以及外來抗原:對外來抗原產生反應而消滅外來威脅、保護人體;而對自體抗原有耐受性,避免攻擊自身。所謂「免疫耐受性」(immune tolerance)係指免疫系統對於某些抗原的不反應性。近年來研究發現有一群T細胞,又名「調節性T細胞」(regulatory T cells)對於周邊免疫耐受性(peripheral tolerance)扮演了極重要的角色。調節性T細胞主動地抑制自體免疫疾病及過敏反應的產生,維持免疫系統的恒定。現已發現一轉錄因子—Foxp3可做為調節性T細胞的分子標記,而且在生理情況下調節性T細胞的分化與發育必須要有Foxp3分子的表現。許多研究團隊已發現若使未分化的T細胞過度表現Foxp3,可有效誘導其分化為調節性T細胞,並且這群「調節性T細胞」有治癒自體免疫疾病或是過敏疾病的療效。另外引起我們注意的是細胞激素—TGF-β。TGF-β是一個多功用的分子,特別是一種抑制免疫反應的細胞激素。許多研究報告已指出TGF-β參與調節性T細胞引起的免疫耐受性,但其機制未明。
在此研究中,我們製作了帶有轉錄因子Foxp3的重組慢病毒(recombinant lentivirus)以及帶有TGF-β的重組慢病毒,用這兩株病毒分別感染T細胞株,使其過度表現Foxp3或是TGF-β,而顯現調節性T細胞的表型。接著我們研究了在這些被病毒感染的細胞株中,Foxp3的表現量、TGF-β分子分泌量,以及在細胞膜上TGF-β分子的表現量的調節。而後我們研究了Foxp3或是TGF-β過度表現是否會調節一些參與TGF-β訊息傳遞路徑的分子,如TGF-β受器,Smad2以及Smad3。我們發現T 細胞株被帶有TGF-β的重組慢病毒感染而過度表現TGF-β之後,被刺激後,介白質-2的分泌量會下降,且會誘發表現Foxp3。而若以同樣方法使T細胞株表現Foxp3,在刺激過後,TGF-β受器,第二型TGF-β以及Smad3的表現量都會上升。而過度表現Foxp3的T細胞株在被TGF-β1刺激之後,Smad2磷酸化的情形會較一般的T細胞株更為明顯。這些研究結果進一步探討了轉錄因子Foxp3誘導T細胞分化為調節性T細胞的機轉,以及TGF-β如何調節免疫抑制功能,並了解Foxp3以及TGF-β的相互作用,以更加闡明調節性T細胞發育與其作用的分子機制。 The immune system has evolved the mechanisms to recognize and eliminate threats, as well as to avoid deleterious responses such as self-destruction and inflammation. Such unresponsiveness to self-antigens and nonpathogenic environmental antigens is called immune tolerance. Regulatory T cells (Tregs) have been demonstrated to play a critical role in maintaining immune tolerance and homeostasis by actively suppressing the development of autoimmune and allergic responses. It has already been reported that the forkhead family transcription factor Foxp3 is critically important for the development and function of the regulatory T cells. It is expressed in CD4+ CD25+, but not CD4+ CD25- T cells and acts as a silencer of cytokine gene promoters in CD4+ CD25+ Treg cells. In addition, studies have shown that the cytokine TGF-β produced by Tregs potently suppresses immune responses. Nonetheless, little is known about the correlation between Foxp3 and TGF-β. In this study, we investigated the effect of overexpression of TGF-β through lentiviral system upon IL-2 secretion and Foxp3 expression in human leukemia cells. Likewise, we investigated the effect of Foxp3 overexpression on the protein level of TGF-β and the components of TGF-β-mediated signaling cascade, such as Smad2 and Smad3. Finally, we examined the effect of Foxp3 on TGF-β1 signaling. We addressed that TGF-β overexpression suppresses stimulation-induce IL-2 hypersecretion and induces Foxp3 expression. Overexpression of Foxp3 had little influence on TGF-βsecretion while significantly enhanced surface-bound TGF-β TGF-βRII and Smad3. Furthermore, we described that Foxp3-overexpressed T cells were more susceptible to TGF-β1-induced phosphorylation of Smad2. These findings help to elucidate the molecular mechanisms of development and action of regulatory T cells. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/31911 |
Fulltext Rights: | 有償授權 |
Appears in Collections: | 口腔生物科學研究所 |
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