2013-01-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/656739摘要：樹突細胞是屬於先天性免疫系統的一個成員，專精於處理及呈獻抗原並啟動及調控適應性免疫反應。在不同種類的樹突細胞中，漿狀樹突細胞(pDC)是最獨特的，因為它們的形態像漿細胞而功能則是在細胞受感染時產生第一型干擾素 (IFN-I)。pDC 在沒有感染的狀況下異常產生的IFN-I 和自體免疫疾病如紅斑性狼瘡(SLE)、牛皮癬(psoriasis)、修格連氏(Sjögren＇s)症候群的發生有相當密切的關係。然而調控pDC 的分化及功能的訊號至今仍不清楚。我們藉由對IFN-I 受體剔除小鼠(IFNAR1KO)的研究發現到樹突細胞尤其是pDC 的分化有明顯的缺失。我們同時也分別在STAT1 剔除鼠及STAT2 低表現突變鼠身上看到類似的表徵，這兩種異常鼠都是在IFN-I 訊息傳遞有嚴重的缺陷。我們藉Flt3 配體(FL)在體外促進共同淋巴先驅細胞(CLP)分化成樹突細胞的過程進而研究IFN-I 可能的作用機轉。雖然CLP 可經由FL 的刺激而分別產生cDC 及pDC，很顯然的pDC 的產生需要Flt3 傳遞較強的訊號同時再加上IFN-I 的作用。在低劑量FL 存在下，CLP 主要是產生cDC，而高劑量FL 則促使pDC 的生成。在缺乏IFN-I 受體的情況下，體內及體外形成pDC 能力都明顯受損。這些結果暗示著FL 和IFN-I 具有協同作用，去促進pDC 從CLP 分化而成。有趣的是，FL 可刺激CLP 產生IFN-I。而IFN-I 則可進一步提高CLP 的Flt3 的表現及促進pDC 的分化。綜合以上結果，我們發現FL 和IFN-I 可以協力去促成CLP 分化成為pDC，這個發現可以幫忙提供一個標的物去做自體免疫疾病的標靶治療。因此我們想藉由以下實驗進一步去探究IFN-I 如何調控FL 去促進CLP 分化成pDC 的分子機轉。1. 研究IFN-I 在FL 促進pDC 分化的作用2. 研究IFN-I 對CLP 及pDC 其他先驅細胞的作用3. 研究FL 如何導致CLP 產生IFN-I4. 研究IFN-I 對pDC 功能的影響5. 研究因IFN-I 造成pDC 的缺陷在實驗性自體免疫腦脊髓炎(EAE)發展過程中的生理角色<br> Abstract: Dendritic cell (DC), belonging to the innate immune system, are specialized for antigen processing and presentation, which initiate and orchestrate the adaptive immune response. Among different subsets of DCs, plasmacytoid DCs (pDC)s are the most unique in that they are morphologically plasma-like and functionally type I IFN (IFN-I) producing during infections. Aberrant IFN-I production by pDC in the absence of infection is implicated in autoimmune diseases, including systemic lupus erythematosus (SLE), psoriasis, and Sjögren’s syndrome. However, signals dictating pDC generation and function remain elusive. Using IFNα receptor 1 (IFNAR1) knockout mice, we found that the development of DCs, particularly pDC, was significantly reduced. A similar phenotype was also observed in STAT1KO mice and STAT2 hypomorphic mutant mice in which IFN-I signaling is severely impaired. In vitro development of DC from common lymphoid progenitor (CLP) using Flt3 ligand (FL) was used to dissect the mechanisms. While both cDC and pDC were generated from CLP by FL stimulation, pDC generation required higher signal strength of Flt3 receptor and depended on concurrent IFN-I signaling. While CLP predominantly generated cDC at low dose of FL, pDC preferentially developed at higher cytokine doses. Absence of IFNAR1 impaired FL-dependent pDC formation from CLP in vitro and in vivo. These results suggest a synergism for FL and IFN-I in pDC development from CLP. Interestingly, IFN-I was induced in CLPs in response to FL stimulation, facilitating up-regulation of Flt3 expression on CLPs and their differentiation into pDC. Taken together, these data define a cooperative effect of FL and IFN-I in pDC development from CLP and could provide a therapeutic target for treatment of autoimmune disease. Therefore we propose to further investigate the underlying mechanisms of IFN-I regulated FL-dependent development and function of pDC from CLP. The follows are the specific aims.1. To study the role of IFN-I in FL-dependent pDC development2. To study the effect of IFN-I on CLP and pDC progenitors3. To study the mechanism of FL-induced IFN-I in CLP4. To study the effect of IFN-I on pDC functions5. To study the biological significance of IFN-I-dependent pDC impairment in mouse EAE model第一型干擾素漿狀樹突細胞Type I IFNPlasmacytoid DC