臺灣博碩士論文加值系統

干擾素 (包含第一型和第二型干擾素)是一種能夠調控先天性和適應性免疫反應的多功能的細胞激素。STAT1是第一型和第二型干擾素共同的訊息傳遞因子。然而，STAT1在抗體反應中扮演的角色目前尚不明確。本論文中，我們證明STAT1正向調控胸腺依賴性與胸腺非依賴性抗原引發的IgG反應，而且此反應是和B淋巴球和T淋巴球的作用有關。此外，STAT1也正向調控IL-4加上CD40抗體以及TLR誘導的IgM反應，而且這個作用在MZ B比FO B顯著。我們進一步發現，STAT1調控TLR誘導的IgM反應是和干擾素的作用無關。Stat1基因剔除的MZ B在受TLR配體刺激後的活化狀態、分裂能力和細胞凋亡的能力並沒有受到影響，但分化成漿細胞和產生IgM的能力則有缺失。有趣的是，我們發現STAT1能和Prdm1(BLIMP-1蛋白的基因名)的啟動子(promoter)結合，進而調控Prdm1 RNA的表現量。而且在經過TLR配體刺激後的Prdm1 RNA表現量在Stat1基因剔除MZ B確實減少。在Stat1基因剔除的MZ B中提高BLIMP-1表現，可以恢復TLR誘導IgM到正常的表現量。TLR誘導Prdm1基因減少的現象，除了Stat1基因剔除的MZ B之外，在脾臟B-1a細胞也可以觀察到。此外，我們發現Stat1基因剔除小鼠對於肺炎鏈球菌的感染比較敏感。靜脈注射肺炎鏈球菌感染後的野生型小鼠的血清，可以保護Stat1基因剔除小鼠免於肺炎鏈球菌感染造成的死亡。我們也證明Stat1基因剔除小鼠對肺炎鏈球菌感染較敏感確實是因為該小鼠MZ B缺少STAT1的緣故。總而言之，我們的實驗結果證明STAT1對於胸腺依賴性和胸腺非依賴性抗原誘導B淋巴球的分化、IgM和IgG的產生扮演著重要的角色。

Interferon (IFN), including type I and II IFNs, are pleiotropic cytokines that modulate the innate and adaptive immunity. STAT1 is a shared signaling mediator of type I and II IFNs. However, the role of STAT1 in antibody responses remains elusive. Here, we demonstrate that STAT1 positively regulates IgG responses in a B cell- and T cell-dependent manner in response to both thymus-dependent (TD) and thymus-independent (TI) antigens. Moreover, STAT1 also positively regulates IL-4 and anti-CD40 antibody- or TLR-mediated IgM responses of B cells which is more prominent in marginal zone B (MZ B) than follicular B (FO B) cells. Further, the STAT1-mediated IgM response of MZ B cells upon TLR stimulation is IFN-independent. While activation, proliferation and apoptosis are not affected, both differentiation into plasma cells and IgM production are impaired in Stat1-/-MZ B cells. Interestingly, STAT1 directly regulates the expression of Prdm1 (encodes BLIMP-1) by binding to its promoter, and Prdm1 expression is reduced in Stat1-/- MZ B cells. Restoration of BLIMP-1 to cells rescues TLR- induced IgM response. The attenuated Prdm1 expression in response to TLR is observed not only in Stat1-/- MZ B cells but also in Stat1-/- splenic B-1a cells. Moreover, Stat1-/- mice are more susceptible to S. pneumoniae infection, which can be rescued by the serum of bacteria primed WT mice. The increased susceptibility to S. pneumoniae infection in Stat1-/- mice is also intrinsic to STAT1 requirement in MZ B cells. Collectively, these results reveal a role of STAT1 in B cell differentiation, and IgM and IgG response to TD and TI antigens.

Table of contents
致謝------------------------------------------------------------------------------------------------- i
Abbreviation----------------------------------------------------------------------------------- iii
摘要------------------------------------------------------------------------------------------------ iv
Abstract------------------------------------------------------------------------------------------ v
Chapter I. Introduction
1.1 Interferons-------------------------------------------------------------------------------------- 2
1.2 Jak-Stat pathway------------------------------------------------------------------------------- 4
1.3 B cell subsets----------------------------------------------------------------------------------- 5
1.4 Transcription factors regulate B cell differentiation-------------------------------------- 7
1.5 TLR and antibody responses----------------------------------------------------------------- 8
1.6 IFNs and antibody responses---------------------------------------------------------------- 9
1.7 Antibody responses and blood-borne bacteria------------------------------------------- 10
1.8 Rational and significance------------------------------------------------------------------- 10
Chapter II. Materials and Methods
2.1 Mice------------------------------------------------------------------------------------------- 16
2.2 Immunization--------------------------------------------------------------------------------- 16
2.3 Antibodies and flow cytometry------------------------------------------------------------ 16
2.4 Cell sorting, cell culture and adoptive transfer------------------------------------------- 17
2.5 Enzyme-Linked Immunosorbent Assay (ELISA)----------------------------------------18
2.6 Immunohistochemistry and MZ B capture ability assay------------------------------- 18
2.7 Activation, proliferation, and apoptosis assays------------------------------------------ 19
2.8 ELISPOT assay------------------------------------------------------------------------------ 19
2.9 Complement depletion assay--------------------------------------------------------------- 20
2.10 Quantitative RT-PCR---------------------------------------------------------------------- 20
2.11 In silico analysis---------------------------------------------------------------------------- 21
2.12 RNA silencing------------------------------------------------------------------------------ 21
2.13 Chromatin immunoprecipitation assay (ChIP)----------------------------------------- 22
2.14 Reporter assay------------------------------------------------------------------------------ 23
2.15 Retroviral transduction-------------------------------------------------------------------- 24
2.16 Priming and challenging of S. pneumoniae--------------------------------------------- 24
2.17 Western blotting---------------------------------------------------------------------------- 25
2.18 Statistical analyses------------------------------------------------------------------------- 25
Tables
Table 1. Antibodies------------------------------------------------------------------------------ 13
Table 2. Reagents--------------------------------------------------------------------------------- 15
Table 3. Primer sequences of RT-QPCR----------------------------------------------------- 21
Table 4. shRNA sequence----------------------------------------------------------------------- 22
Table 5. Primer sequences of ChIP------------------------------------------------------------ 23
Chapter III. Results
3.1 Impaired antibody response in Stat1-/- mice to TD antigen-----------------------------27
3.2 Impaired IgG responses to TD antigen are intrinsic to the loss of STAT1 in T cells-------------------------------------------------------------------------------------------------------- 28
3.3 Impaired IgM and IgG response to TD antigen are intrinsic to the loss of STAT1 in B cells---------------------------------------------------------------------------------------------- 28
3.4 IL-4 and anti-CD40 antibody-induced IgM and IgG1 responses are impaired in Stat1-/-B cells--------------------------------------------------------------------------------------------- 29
3.5 IgM responses are normal in Stat1-/- mice when TNP-OVA emulsified with IFA or alum------------------------------------------------------------------------------------------------ 29
3.6 Impaired IgM response to CFA in Stat1-/- mice----------------------------------------- 30
3.7 TI-II antigen-induced IgG, but not IgM, responses are impaired in Stat1-/- mice--- 30
3.8 Impaired IgM responses in Stat1-/- B cells in response to TLR stimulation --------- 31
3.9 Impaired IgM response in Stat1-/- MZ B cells in response to TLR stimulation ----- 31
3.10 Impaired TLR-induced IgM responses in Stat1-/- mice are intrinsic to MZ B cells--------------------------------------------------------------------------------------------------------- 32
3.11 Development, distribution and antigen-capture ability of MZ B are normal in Stat1-/- mice---------------------------------------------------------------------------------------------- 33
3.12 The expression of TLR and TLR-induced activation of MZ B are normal in the absence of STAT1--------------------------------------------------------------------------- 34
3.13 TLR-stimulated B cell differentiation is impaired in the absence of STAT1-------- 35
3.14 STAT1 positively regulates Prdm1 expression and restoration of BLIMP-1 rescues the impaired IgM response in Stat1-/-MZ B cells--------------------------------------------- 36
3.15 Stat1-/- mice are more susceptible to blood-borne S. pneumoniae infection--------- 37
3.16 Increased susceptibility to S. pneumoniae infection in Stat1-/- mice is intrinsic to STAT1 requirement in MZ B cells------------------------------------------------------------ 38
3.17 Impaired LPS-induced production of anti-PC IgM in the absence of STAT1------ 40
3.18 TLR- and S. pneumoniae-stimulated serine phosphorylation of STAT1 contributes to the IgM response in MZ B cells-------------------------------------------------------------- 40
3.19 TLR-mediated Prdm1 expression and IgM response are impaired in Stat1-/- splenic B-1a cells------------------------------------------------------------------------------------------ 42
Chapter IV. Discussion
4.1 STAT1 regulates IgG response dependent on IFNs and adjuvant---------------------- 44
4.2 Distinct requirement of Stat1 and IFN in immune cells ------------------------------- 44
4.3 Stat1 directly regulates Prdm1 expression ----------------------------------------------- 45
4.4 IL-10 synergizes with TLR to promote Stat1 DNA binding ability to Prdm1 promoter ------------------------------------------------------------------------------------------ 46
4.5 The role of Stat1 in S. pneumoniae clearance ------------------------------------------- 47
4.6 The role of pS727-Stat1 in immune cells ------------------------------------------------ 48
4.7 The role of Stat1 in regulating MZ B and spB-1a differentiation -------------------- 49
4.8 The role of Stat1 in regulating nature antibody production --------------------------- 49
4.9 Concluding remarks------------------------------------------------------------------------- 50
Reference--------------------------------------------------------------------------------------- 51
Chapter V. Figures
Figure 1. TD antigen-induced IgM and IgG responses to TD antigen are impaired in Stat1-/- mice---------------------------------------------------------------------------------------- 61
Figure 2. Impaired IgG responses in Stat1-/- mice are T cell intrinsic--------------------- 63
Figure 3. Impaired IgM and IgG responses in Stat1-/- mice are B cell intrinsic---------- 65
Figure 4. IL-4 and anti-CD40 antibody-induced IgM production are impaired in Stat1-/- B cells---------------------------------------------------------------------------------------------- 67
Figure 5. TD responses in Stat1-/- mice is normal when antigen is emulsified with alum-------------------------------------------------------------------------------------------------------- 69
Figure 6. CFA-induced IgM response are impaired in Stat1-/- mice----------------------- 70
Figure 7. TI-II antigen-induced IgG, but not IgM, responses are impaired in Stat1-/- mice------------------------------------------------------------------------------------------------ 71
Figure 8. TLR-induced IgM and IgG responses are impaired in Stat1-/- B cells----------72
Figure 9. Impaired TLR-induced IgM responses in Stat1-/- MZ B are type I- and II- IFN independent--------------------------------------------------------------------------------------- 73
Figure 10. Impaired TLR-induced IgM responses in Stat1-/- mice are intrinsic to defect in MZ B cells-------------------------------------------------------------------------------------- 74
Figure 11. MZ B development, distribution and antigen-capture ability are normal in Stat1-/- mice--------------------------------------------------------------------------------------- 75
Figure 12. The expression of TLR and activation markers are comparable between WT and Stat1-/-MZ B cells--------------------------------------------------------------------------- 77
Figure 13. IL-10 but not IL-6 or TNF-a is decreased in Stat1-/-MZ B upon TLR stimulation---------------------------------------------------------------------------------------- 79
Figure 14. TLR-induced proliferation and apoptosis of Stat1-/-MZ B cells are normal---------------------------------------------------------------------------------------------------------- 81
Figure 15. TLR-stimulated B cell differentiation is impaired in Stat1-/-MZ B cells---- 82
Figure 16. TLR-induced Prdm1 and Xbp1s expression are reduced in Stat1-/-MZ B cells------------------------------------------------------------------------------------------------- 84
Figure 17. IgM production and Prdm1 expression is decreased in STAT1 knockdown CH12F3 cells-------------------------------------------------------------------------------------- 86
Figure 18. STAT1 binds to Prdm1 promoter region and regulates Prdm1 expression----------------------------------------------------------------------------------------------------------- 87
Figure 19. Restored Blimp-1 rescues TLR-induced IgM responses in Stat1-/-MZ B cells------------------------------------------------------------------------------------------------------- 89
Figure 20. MZ B plays a role in S. pneumoniae clearance---------------------------------- 90
Figure 21. Stat1-/- mice are more susceptible to S. pneumoniae infection---------------- 91
Figure 22. WT serum transfer rescues Stat1-/- mice from S. pneumoniae infection and anti-PC IgM plays a role in S. pneumoniae clearance--------------------------------------- 93
Figure 23. Increased susceptibility to S. pneumoniae infection in Stat1-/- mice is intrinsic to the loss of STAT1 in MZ B cells------------------------------------------------------------ 94
Figure 24. Reduced production of PC-specific antibody in Stat1-/- mice following S.
pneumoniae and TLR stimulation-------------------------------------------------------------- 96
Figure 25. p38 and CDK8 inhibitors reduce TLR-induced IgM responses in WT MZ B cells------------------------------------------------------------------------------------------------- 97
Figure 26. Serine phosphorylation of STAT1 regulates IgM production from MZ B cells------------------------------------------------------------------------------------------------- 99
Figure 27. Impaired IgM response in Stat1-/- spB-1a cells-------------------------------- 101
Figure 28. The percentage and numbers of peritoneal B-1a and B-1b cells are normal in
Stat1-/- mice-------------------------------------------------------------------------------------- 103
Figure 29. STAT1 positively regulates TLR-mediated plasma cell differentiation through directing binding to Prdm1 promoter, which is crucial for clearance of bloodborne
bacteria------------------------------------------------------------------------------------104
Appendix
STAT1 regulates marginal zone B cell differentiation in response to inflammation and infection with blood-borne bacteria
J. Exp. Med. 2016 Vol. 213 No. 13 3025–3039

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