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研究生:沈冠印
研究生(外文):Kuan-Yin Shen
論文名稱:脂質化胜肽抗癌應用與抗原呈獻分子機制之探討
論文名稱(外文):Anti-tumor Effects and Antigen Presentation Mechanisms of Toll-like Receptor 2 (TLR2) agonist-conjugated peptide
指導教授:劉士任
指導教授(外文):Shih-Jen Liu
口試委員:冷治湘廖光文沈家瑞莊宗顯劉士任
口試委員(外文):Chih-Hsiang LengKuang-Wen LiaoChia-Rui ShenTsung-Hsien ChuangShih-Jen Liu
口試日期:2014-04-30
學位類別:博士
校院名稱:國防醫學院
系所名稱:生命科學研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:英文
論文頁數:69
中文關鍵詞:脂質胜肽交叉呈獻樹突狀細胞免疫療法人類乳突病毒子宮頸癌
外文關鍵詞:Di-palmitoylated peptideCross-presentationDendritic cellImmunotherapyHuman PapillomavirusCervical cancer
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樹突狀細胞近期文獻指出雙棕櫚酸化胜肽(di-palmitoylated peptide)可以增加胜肽疫苗的免疫原性,但對於雙棕櫚酸化胜肽之抗原交叉呈獻的分子機制尚未明瞭。本論文以Pam2IDG和Pam2EQL作為模型,進一步探討脂質化胜肽透過先天免疫路徑調節抗原呈獻的機制。首先,我們發現抗原呈獻細胞之樹突細胞表面上的類鐸受體2(Toll-like receptor, TLR2)能經由網格蛋白媒介胞吞作用(clathrin-mediated endocytosis)促進雙棕櫚酸化胜肽進入細胞內。以雙棕櫚酸化胜肽處理的樹突狀細胞則可以透過TLR2誘發抗腫瘤免疫反應。另外,我們發現樹突細胞不需要透過抗原處理相關運輸分子(Transporter associated with antigen processing, TAP)的參與呈獻雙棕櫚酸化胜肽以活化殺手T細胞。因此,我們進一步利用奎寧(chloroquine)阻斷液泡酸化以及組織蛋白酶S(Cathepsin S)抑制劑(Z-FL-COCHO)阻斷液泡系統呈獻路徑來觀察。結果發現,此兩種抑制劑皆能阻斷雙棕櫚酸化胜肽的抗原呈獻。因此,雙棕櫚酸化胜肽經由液泡呈獻路徑。為了瞭解其機制,我們探索雙棕櫚酸化胜肽在細胞內的所在位置。從而發現此胜肽由早期液泡進入到晚期液泡,並且在晚期液泡和溶小體發現抗原胜肽與第一型主要組織相容性抗原和胜肽表位的複合體。另一方面,我們發現調控液泡發育的Rab7蛋白表現可受到TLR2路徑的調控。此外,我們發現增加Rab7表現能促進樹突狀細胞呈獻雙棕櫚酸化胜肽而活化殺手T細胞。綜合以上結果,我們發現TLR2媒介抗原交叉呈獻可藉由增加Rab7表現和透過液泡路徑而促進殺手T細胞的活化。
Dendritic cells (DCs) can process and present extracellular antigens on MHC class I molecules to activate cytotoxic T lymphocyte (CTL) responses through an important mechanism, antigen cross-presentation. However, toll-like receptor (TLR)-mediated cross-presentation of extracellular antigens by DCs remains unclear. In this study, models of synthetic di-palmitoylated peptides (Pam2IDG and Pam2EQL) explored the mechanisms of TLR2-mediated cross-presentation. We observed that TLR2 facilitated the internalization of di-palmitoylated peptides by bone marrow-derived DCs (BMDCs) via clathrin-mediated endocytosis. The immunization of di-palmitoylated peptide-pulsed BMDCs induced tumor regression through TLR2 signaling. These findings indicated that exogenous TLR2 agonist-conjugated peptide could be cross-presented to CTL. We further identified di-palmitoylated peptides-induced antigen-specific CTL responses was transporter associated with antigen processing (TAP) independent. In addition, endosomal acidification inhibitor (chloroquine) or a lysosomal degradation inhibitor (Z-FL-COCHO) could block the presentation of di-palmitoylated peptides by MHC class I molecules. The endocytosed di-palmitoylated peptide was delivered rapidly from early endosome antigen-1 (EEA1)-positive endosomes to RAS-related GTP-binding protein 7 (Rab7)-associated late endosomes compared with their non-lipidated counterparts. Furthermore, we found that the Rab7 expression co-related was up-regulated by di-palmitoylated peptide was via the TLR2/MyD88 pathway. Therefore, di-palmitoylated peptide could be cross-presented efficiently via vacuolar pathway to enhance CTL responses though TLR2 signaling. In conclusion, our data suggest that TLR2-mediated cross-presentation is through the upregulation of Rab7 and a vacuolar pathway to prime CTL responses.
I. Introduction...............................................................................................................................1
1. Antigen presentation................................................................................................................1
1.1. Dendritic cells are antigen-presenting cells for T cell activation.............................................2
1.2. MHC class I and MHC class II pathway of antigen presentation...............................................2
1.3. Antigen cross-presentation for CTL activation.......................................................................3
1.4. Receptor-mediated antigen cross-presentation.....................................................................4
2. Toll-like receptor 2 recognizes lipopeptides.............................................................................5
2.1. Toll-like receptors.................................................................................................................5
2.2. TLR2 is paired with TLR1 or TLR6 to recognize lipopeptides..................................................6
3. Human papillomavirus-associated cervical cancer ....................................................................6
3.1 The progression of HPV associated cervical cancer.................................................................6
3.2 Approaches of cervical cancer vaccines..................................................................................7
4. Palmitoylated peptides.............................................................................................................9
5. The motivation of study...........................................................................................................10
II. Materials and Methods.............................................................................................................12
1. Animals...................................................................................................................................12
2. Peptides and di-palmitoylated peptides...................................................................................12
3. BMDC generation and maturation analysis...............................................................................12
4. ELISPOT assay..........................................................................................................................13
5. Animal tumor model................................................................................................................14
6. Internalization assay................................................................................................................15
7. Laser scanning confocal microscopy.........................................................................................15
8. Western blotting......................................................................................................................16
9. In vitro cross-presentation assay.............................................................................................17
10. In vivo T cell cytotoxicity assay..............................................................................................17
11. Lentivirus preparation............................................................................................................18
12. Statistical analysis..................................................................................................................19
III. Results....................................................................................................................................20
1. Di-palmitoylated peptide could enhance immune responses....................................................20
1.1 Pam2IDG promoted BMDCs maturation..................................................................................20
1.2 TLR2 is paired with TLR6 for BMDCs maturation by Pam2IDG stimulation...............................20
1.3 Pam2IDG enhances CTL responses via TLR2/6.......................................................................21
1.4 TLR2 is required for di-palmitoylated peptide cross-presentation.........................................22
1.5 TLR2 is required for Pam2IDG-pulsed BMDC to induce tumor regression...............................23
2. The roles of TLR2 in di-palmitoylated peptides cross-presentation.........................................24
2.1 TLR2 facilitates Pam2IDG endocytosis by BMDCs ...................................................................24
2.2 The cross-priming mediated by di-palmitoylated peptides is TAP independent.....................25
2.3 Di-palmitoylated peptides co-localize with Rab7+ and LAMP1+ endolysosomes...................28
2.4 The epitope/MHC I complex is formatted at Rab7+ and LAMP1+ endolysosome....................29
2.5 Di-palmitoylated peptides upregulate Rab7 expression to promote cross-presentation.........31
2.6 The therapeutic effects of Pam2IDG on different tumor models..............................................33
IV. Discussion...............................................................................................................................34
V. Conclusion...............................................................................................................................38
VI. Table and Figures....................................................................................................................39
VII. References..............................................................................................................................64

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