- 주제(키워드) IL-33 , NLRP3 , Th17 , Treg , DC , Cell differentiation
- 발행기관 고려대학교 대학원
- 지도교수 김태성
- 발행년도 2020
- 학위수여년월 2020. 2
- 학위구분 박사
- 학과 대학원 생명과학과
- 세부전공 분자의생명과학 전공
- 원문페이지 128 p
- UCI I804:11009-000000127159
- DOI 10.23186/korea.000000127159.11009.0000951
- 본문언어 영어
- 제출원본 000046025498
초록/요약
Regulation of Th17/Treg balance is important for induction of inflammation or maintenance of homeostasis. Although the mechanism of Th17/Treg differentiation has been well reported, the effects of exogenous and endogenous molecules as pro-inflammatory factors on Th17/Treg balance is not well understood. In this thesis, it was investigated whether both interleukin (IL)-33 and NOD-like receptor family protein 3 (NLRP3) regulate the differentiation of Th17/Tregs and their responses. IL-33 is associated with a variety of inflammatory diseases, such as sclerosis, inflammatory bowel disease, rheumatoid arthritis, and asthma. While IL-33 is mainly involved in the induction of Th2, the effect of IL-33 on the balance of Th17/Treg is still largely unknown. As DCs are essential cells for presenting antigens to CD4+ T cells under inflammatory disease conditions, the result of IL-33 on CD4+ T cells immunity through DC-mediated effects was investigated. IL-33 induces the maturation of DCs, which express the IL-33 receptors, to present self-antigens and to increase production of pro-inflammatory cytokines such as IL-1β and IL-6. IL-33-matured DCs (IL-33-matDCs) enhanced T cell activation and Th17 differentiation via IL-1β and IL-6, whereas it inhibited Treg differentiation. Moreover, stable Tregs (CD25hiCD4+ Tregs) were dramatically converted to IL-17-producing cells during co-culture with IL-33-matDCs, while unstable Tregs (CD25loCD4+ Tregs) showed a decrease in Foxp3 expression and slightly shifted. The stable Tregs expressed high levels of IL-6 receptors, indicating that the greater propensity of stable Tregs compared to unstable Tregs to convert to Th17 is due to IL-6 signaling. Taken together, these results show that IL-33 breaks the Th17/Treg balance thereby leading to Th17 responses via DC-dependent pathway through regulation of Th17/Treg differentiation and converting Tregs to Th17. NLRP3 is mainly known to be involved in inflammasome activation associated with several diseases. Recently, the expression of NLRP3 in CD4+ T cells, as well as in myeloid cells has been described. However, the role of T cell–intrinsic NLRP3 in Treg differentiation remains unknown. Here, NLRP3 impeded the expression of Foxp3 independent of inflammasome activation in Tregs. Notably, the levels of Tregs were higher in various organs of NLRP3-dificient mice than those of wild-type mice. NLRP3 deficiency increased the amount of Treg populations and suppressive activity, whereas NLRP3 overexpression reduced Foxp3 expression and Treg abundance. Importantly, NLRP3 interacted with Kpna2 and translocated to the nucleus from the cytoplasm under Treg-polarizing conditions. Both alleviation of colitis and faster tumor progression, which are usually associated with an increased Treg frequency were observed in NLRP3-deficient mice. Altogether, NLRP3 has a novel role as a new negative regulation of Treg differentiation, mediated via its interaction with Kpna2 for nuclear translocation. In conclusion, these studies are helpful to understand the mechanism of T cell differentiation in the inflammatory conditions of increasing IL-33 or upregulating NLRP3, and also provide a rational for curing inflammatory diseases.
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LIST OF FIGURES
LIST OF ABBREVIATIONS
ABSTRACT
OVERVIEW
Implication of network in the differentiation of Th17 and Tregs
1. Dendritic cells (DCs)
2. T helper 17 cells (Th17) and regulatory T cells (Tregs)
1) Th17
2) Tregs
2-1) Treg suppressive mechanisms against effector T cells (Teff)
2-2) Control of Foxp3 expression
3) Reciprocal development of Th17 and Tregs
4) Conversion of Tregs to Th17
3. Interleukin-33 (IL-33)
4. NOD-like receptor family protein 3 (NLRP3)
REFERENCES
CHAPTER I
IL-33-matDCs induce the differentiation of Th17 and the conversion of Tregs toward Th17
ABSTRACT
INTRODUCTION
MATERIALS & METHODS
RESULTS
1. IL-33 matures and activates DCs to act on T cells.
2. IL-33 induces maturation of DCs, stimulating CD4+ T cell activation.
3. IL-33 enhances the differentiation of Th17 through DC maturation.
4. IL-33-matDCs enhance the differentiation of Th17 through secretion of IL-1β and IL-6 in vitro.
5. IL-33-matDCs upregulate the Th17 responses in vivo.
6. IL-33 inhibits DC-mediated Treg differentiation.
7. IL-33-matDCs induce the conversion of stable Tregs to Th17.
8. IL-6 is involved in the conversion of stable Tregs into Th17 by IL-33-matDCs.
9. The conversion of Tregs into Th17 by IL-33-matDCs is dependent on cell contact.
DISCUSSION
REFERENCES
CHAPTER II
NLRP3 negatively regulates Treg differentiation through Kpna2-mediated nuclear translocation
ABSTRACT
INTRODUCTION
MATERIALS & METHODS
RESULTS
1. NLRP3 deficiency increases the generation of Tregs.
2. NLRP3 impedes the expression of Foxp3 in iTregs.
3. NLRP3 expression is different between Teff cells and iTregs.
4. NLRP3 activity is independent of inflammasome activation in iTreg responses.
5. NLRP3 translocates to the nucleus by interacting with Kpna2 in iTregs.
6. NLRP3-deficient iTregs have more suppressive ability than wild-type iTregs.
7. NLRP3 deficiency relieves the induction of colitis via elevated Tregs.
8. NLRP3 deficiency progresses tumor growth by enhancing Treg populations.
DISCUSSION
REFERENCES
FINAL CONCLUSIONS
APPENDICES
ABSTRACT IN KOREAN
CURRICULUM VITAE
ACKNOWLEDGEMENTS
