臺灣博碩士論文加值系統

宿主對抗外來抗原的免疫機制分成與生俱來的先天性免疫反應與適應性免疫反應。而在適應性免疫中，具有專一性的T細胞免疫在傳統上可以分成第一型與第二型的T細胞免疫反應─分別可分泌IFN-g及IL-4。直到最近，一種新發現獨立於此的新的CD4 T細胞─「第十七型CD4 T細胞」(TH17)，被發現到可以宰控在促發炎性的自體免疫疾病裏的免疫反應。

為了研究這種第十七型CD4 T細胞的轉錄層次的調控，我們的研究首先利用一種條件式STAT3剔除的動物模型—在此模型裏STAT3基因條件式地在CD4及CD8 T細胞裏被剔除，發現到STAT3是第十七型CD4 T細胞的主要調控因子。STAT3轉錄分子的磷酸化促進第十七型CD4 T細胞分泌IL-17，而在CD4 T細胞的STAT3剔除阻斷了兩種自體免疫疾病模型(自體免疫肺炎與實驗性自體免疫性腦炎)的發炎反應。以單株抗體阻斷IL-17與IL-23接受器則可以延長自體免疫肺炎小鼠的存活，印證了我們在基因剔除小鼠身上的發現。

接著我們進一步發現在CD8 T細胞也可以觀察到一種分泌IL-17的新型第十七型CD8 T細胞(Tc17)。我們純化分離這群細胞進行體內及體外的表現型與功能分析。第十七型CD8 T細胞所分泌的細胞激素及表現的接受器、轉錄分子等，均與傳統的第一型與第二型CD8 T細胞不同，這種新型的第十七型CD8 T細胞也需要ROR-gt的活化與STAT3轉錄分子的磷酸化來分泌IL-17。功能性的分析發現分泌第十七型CD8 T細胞在體外不具有細胞毒殺功能。然而，經由被動移植注射高度純化、具有抗原專一性的分泌IL-17的第十七型CD8 T到表現抗原的宿主裏，發現它在體內具有功能可塑性，可以轉換成為分泌IFN-g的毒殺細胞，並經過大量增生以後造成病理變化。我們推論第十七型CD8 T細胞比傳統第一型CD8 T細胞更可以有效地應用在感染症或腫瘤免疫治療。

第十七型CD4與第十七型CD8 T細胞免疫反應改寫了許多疾病的病理機轉，我們的研究除了闡明這兩種第十七型CD4與第十七型CD8 T細胞的功能與角色外，也提供了臨床醫學研究對於許多疾病宿主免疫反應的調控治療指引，未來可以用在自體免疫、感染症、腫瘤與移植免疫的相關研究。

The immune system uses two arms, innate immunity and adaptive immunity, to defend host against foreign pathogens. Among adaptive immunity, antigen-specific T cells mediated cellular immunity were traditionally classified as type 1 or type 2 T cells, which secrete IFN-g or IL-4, respectively. Until recently, a new lineage of CD4 T cells, type 17 CD4 (TH17) cells, was found to orchestrate immune response in pro-inflammatory autoimmune diseases.

To investigate the transcriptional control of TH17 differentiation, we first used a conditional knockout model, in which STAT3 gene is deleted in CD4 and CD8 T cells, to identify STAT3 as the master regulator of TH17 development. Phosphorylated STAT3 contributes to IL-17 production in TH17 cells and conditional deletion of STAT3 in CD4 T cells results in abrogation of inflammation in two autoimmune disease models, autoimmune pneumonitis and experimental autoimmune encephalitis. Blockade of IL-17 and IL-23 receptor via monoclonal antibodies prolonged survival in autoimmune pneumonitis mice and thus confirmed the findings in this conditional deletion model.

Our further studies in CD8 T cells defined a novel lineage of type 17 cytotoxic CD8 T cells that secrete IL-17 (Tc17). We purified this subset to characterize its phenotype and function in vitro and in vivo. Tc17 cells require activation of ROR-gt and phosphorylation of STAT3 to produce IL-17 and are different in cytokine production, expression of cytokine receptor and transcription factor from the traditional Tc1 and Tc2. Functional study of Tc17 in vitro showed decreased lytic function. However, adoptive transfer of highly-purified, antigen-specific, IL-17 secreting Tc17 cells to antigen-expressing hosts demonstrated functional plasticity in this CD8 T cell subset, with loss of IL-17 expression and acquisition of IFN-g expression after transfer, as well as increased accumulation and substantial pulmonary pathology as compared with Tc1 CD8 T cells. These studies suggest that adoptive transfer of Tc17 cells may have a role in the therapy of infectious disease and/or cancer.

The identification of type 17 CD4 and CD8 T cells revised the current mechanistic understanding of many diseases. Our studies not only elucidated the role and function of type 17 CD4 TH17 and Tc17 cells but can provide new hints in modulating immune response in clinical settings. These findings could be continued in further studies in autoimmune, infectious disease, cancer and transplantation.

指導教授推薦書………………………………………………………………
口試委員會審定書……………………………………………………………
授權書…………………………………………………………………………iii
ACKNOWLEDGEMENTS …………………………………………………………v
ABSTRACT (CHINESE) ………………………………………………………vi
ABSTRACT (ENGLISH) ……………………………………………………viii
TABLE OF CONTENTS ………………………………………………………x
LIST OF FIGURES …………………………………………………………xiii

CHAPTER 1. INTRODUCTION
1.1 INTRODUCTION ……………………………………………………….2
1.2 ADAPTIVE IMMUNITY ……………………………………………….2
1.3 REVISION OF TH1/TH2 PARADIGM ………………………………6
1.4 IL-17 CYTOKINE AND ITS RECEPTOR …………………………10
1.5 RESEARCH NICHES …………………………………………………12

CHAPTER 2. CD4 TH17 CELLS: THE REQUIREMENT OF STAT3 SIGNALING IN TH17 DEVELOPMENT AND ACTIVATION OF TH17 RESPONSE IN AUTOIMMUNE DISEASE
2.1 INTRODUCTION ……………………………………………………….16
2.2 MATERIALS AND METHODS
2.2.1 Mice …………………………………………………………………20
2.2.2 In vitro activation of T cells …………………………21
2.2.3 Isolation of gut associated lymphocytes ……………21
2.2.4 Experimental Autoimmune Encephalitis (EAE) induction ………………............................................22
2.2.5 Autoimmune pneumonitis ……………………………………23
2.2.6 Recombinant vaccinia virus…………………………..…24
2.2.7 Flow cytometry and intracellular staining (ICS)…24
2.2.8 Quantitative PCR ………………………………………………24
2.3 RESULTS
2.3.1 Generation of mice with STAT3 deficient CD4 T cells …………………...26
2.3.2 Endogenous TH17 are absent in STAT3-/- CD4 mice …………………..….27
2.3.3 Experimental autoimmune encephalomyelitis is mitigated in STAT3-/- CD4 mice …………………………………………………………..…………...28
2.3.4 STAT3 signaling is required for TH17-dependent autoimmune pneumonitis …………………………………………………………..…...30
2.3.5 Fatal autoimmune pneumonitis requires IL-17 / IL-23R / STAT3 signaling ………………………………………………………………...…33
2.4 DISCUSSION …………………………………………………………………..35

CHAPTER 3. CD8 Tc17 T CELLS: FUNCTIONAL PLASTICITY AND SUBSET DIVERSITY
3.1 INTRODUCTION ………………………………………………………..……..52
3.2 MATERIALS AND METHODS
3.2.1 Mice ………………………………………………………………….…….55
3.2.2 CD8 T cell polarization …………………………………………………….56
3.2.3 Flow cytometry and intracellular staining (ICS) ………………………..…56
3.2.4 Enrichment and purification of viable Tc subsets based on cytokine profile (Cytokine-Secretion Assay) …………………..………………………...…57
3.2.5 In vitro CTL assay ………………………………………………………….58
3.2.6 Recombinant vaccinia virus and Listeria monocytogenes ………………....59
3.2.7 Adoptive transfer …………………………………………………………...60
3.2.8 Quantitative real-time PCR …………………………………….…………..61
3.2.9 Histopathology…………………………………………………………...…61

3.3 RESULTS
3.3.1 IL-17 secreting CD8 T cells are phenotypically distinct from Tc1 and Tc2 cells …………………………………………………………………………..62
3.3.2 STAT3 is required for Tc17 polarization in vitro and in vivo ..........................63
3.3.3 In vitro polarization determines Tc1 and Tc17 phenotype and function ……..64
3.3.4 Tc17 cells show functional plasticity in vivo ………………………………...66
3.3.5 Adoptive transfer of Tc17 cells results in pulmonary pathology ……………..67
3.4 DISCUSSION…………………………………………………………………...68

CHAPTER 4. CONCLUSION
4.1 SUMMARY…………………………………………………………………......86
4.1 FUTURE WORK……….………………………………………………….........88

REFERENCES ………………………………………..……………………...……90

APPENDIX:
PUBLICATION ………………………………………...…….…………….…..102
SYMPOSIA AND SEMINA ……………………………………………………102


LIST OF FIGURES
Figure 2-1: Conditional deletion of STAT3 in CD4 lymphocytes from CD4-Cre x STAT3flox mice………………………………………………….……39
Figure 2-2: TH17 skewing requires STAT3 expression in vitro…………….….…41
Figure 2-3: STAT3 is required in vivo for development of endogenous gut-associated TH17 cells………………………………………..…………………….42
Figure 2-4: STAT3 expression in CD4 T cells is required for activation of TH17 response in experimental autoimmune encephalitis (EAE) induction....43
Figure 2-5: Experimental autoimmune encephalitis (EAE) induction results in CNS inflammation……………………………………………………….…..45
Figure 2-6: Clinical disease score and body weight change in experimental autoimmune encephalitis (EAE)……………………………………….46
Figure 2-7: STAT3 is required for the development of TH17 cells in an autoimmune pneumonitis model……………………………………………………..47
Figure 2-8: CD4 T cell expression of STAT3 is required for the development of fatal autoimmune pneumonitis………………………………………………50
Figure 3-1: In vitro polarization of IL-17 secreting CD8 T cells (Tc17)…………73
Figure 3-2: STAT3 is required for Tc17 differentiation in vitro………………….75
Figure 3-3: STAT3 is required for Tc17 differentiation in vivo………………….76
Figure 3-4: Phenotypic and effector molecule analysis of Tc1 and Tc17 subsets..78
Figure 3-5: Differential gene expression of Tc1 and Tc17 cells………………….79
Figure 3-6: in vitro CTL function of Tc1 and Tc17 cells………............................81
Figure 3-7: In vivo plasticity and persistence of Tc17 cells………………………82
Figure 3-8: Adoptive transfer of IL-17 secreting Tc17 cells results in pulmonary pathology……………………………………………………………….84

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