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研究生:邱奕凱
研究生(外文):Yi-Kai Chiu
論文名稱:轉錄因子ABF-1抑制漿細胞分化但是促進記憶B細胞形成
論文名稱(外文):Transcription Factor ABF-1 Suppresses Plasma Cell Differentiation but Facilitates Memory B Cell Formation
指導教授:林國儀
指導教授(外文):Kuo-I Lin
學位類別:博士
校院名稱:國立陽明大學
系所名稱:微生物及免疫學研究所
學門:生命科學學門
學類:微生物學類
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:76
中文關鍵詞:漿細胞記憶B細胞生產中心B細胞轉錄抑制蛋白
外文關鍵詞:ABF-1Blimp-1plasma cellsmemory B cellsGC B cells
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ABF-1是的一個屬於bHLH家族的轉錄抑制蛋白, ABF-1表現在活化的B細胞以及霍奇金氏淋巴瘤細胞;ABF-1在霍奇金氏淋巴瘤的功能是經由拮抗E蛋白的功能因而抑制B細胞相關的基因;但是ABF-1在人類B細胞上的功能目前還是未知的。在之前的研究指出ABF-1受到轉錄抑制蛋白Blimp-1的調控。Blimp-1經由抑制已活化B細胞以及生長中心B細胞的基因來幫助漿細胞的分化。經由分析人類以及老鼠不同族群的B細胞發現ABF-1以及Msc (老鼠中ABF-1的直系同源基因) 基因主要表現在記憶B細胞,另外利用細胞介白素21以及刺激表面蛋白CD40來活化B細胞變成漿細胞的培養過程中,ABF-1以及Msc的表現先上升,隨著漿細胞的分化而下降。在培養B細胞變成漿細胞的過程中,利用慢病毒轉導表現ABF-1可抑制產生免疫球蛋白G漿細胞之分化,另外利用干擾RNA降低ABF-1的表現可以增加產生免疫球蛋白G漿細胞之分化。另外,我們發現ABF-1抑制活化B細胞的細胞增生進而抑制漿細胞分化。同樣的,利用cDNA微矩陣檢查被ABF-1所調控的基因,結果顯示在ABF-1大量表現的B細胞內,記憶B細胞相關的基因FCRL2和FCRL4表現會增加;然而與分泌抗體以及細胞增生相關的基因IGJ以及FLI1則被ABF-1抑制。此外,我們證明Blimp-1會直接黏結在ABF-1啟動子上面,進而抑制ABF-1基因的轉錄活性。
為了研究ABF-1在活體內的功能,我們生產了一株具B細胞表現專一性,而且需誘導活化ABF-1表現的EμVH-ABF-1-ER基因轉殖小鼠。在老鼠內打入特殊抗原而引起T細胞免疫反應的過程中誘發ABF-1的活性會減少具抗原專一性的漿細胞以及血液中對抗原有專一性抗體的量,這現象在免疫的二次反應也得到相同的結果。然而,在減少漿細胞的過程中,記憶B細胞的數量以及生產中心B細胞的數量是增加的,因此我們猜測ABF-1在生產中心B細胞分化成記憶B細胞的過程中扮演重要的角色。
總結,我們在活體外實驗以及活體內實驗都證實Blimp-1經由抑制ABF-1基因的表現以產生足夠數量的漿細胞;而ABF-1持續表現會促進記憶B細胞的分化。因此調節Blimp-1與ABF-1的軸向是決定已活化B細胞走向漿細胞或者記憶B細胞的重要關鍵。

ABF-1, a basic helix loop helix (bHLH) transcriptional repressor, is expressed in human activated B cells and Hodgkin’s lymphoma. The role of ABF-1 in Hodgkin’s lymphoma is to silence the expression of B cell specific genes by antagonizing E2A function. However, the function of ABF-1 in normal human B cells remains unclear up to date.
ABF-1 is a potential target of Blimp-1, which is a transcriptional repressor that inhibits gene expression program involved in activated B cells and germinal center B cells in order to facilitate plasma cell differentiation. Further analysis of ABF-1 and its mouse orthologue, Msc, expression in B cell subsets, showed that human and mouse memory B cells expressed higher ABF-1 or Msc than naïve B cells. ABF-1 was activated early in human memory B cells stimulated with IL-21 + αCD40 but was down-regulated in plasma cells. Ectopic expression of ABF-1 in IL-21 + αCD40-stimulated human memory B cells reduced IgG-secreting plasma cells, while knockdown of ABF-1 by shRNA generated more IgG-secreting plasma cells. The disturbed plasma cell generation by the levels of ABF-1 in the in vitro differentiation culture was linked with the changes in cell proliferation. Accordingly, microarray analysis of genes subjected to ABF-1 regulation revealed that FCRL2 and FCRL4 associated with memory B cells were up-regulated, whereas IGJ involved in immunoglobulin production and FLI1 involved in cell proliferation were down-regulated by ectopic expression of ABF-1. Furthermore, we demonstrated that ABF-1 was directly repressed by Blimp-1 that binds directly to the promoter region of ABF-1 and inhibits transcriptional activity of ABF-1.
To study the in vivo function of ABF-1, B cell-specific and inducible EμVH-ABF-1-ER transgenic mice were generated. Induction of ABF-1 in primary or secondary immune response results in reduced production of antigen-specific antibody and antigen-specific plasma cells. Furthermore, the population of germinal center B cells and memory B cells were amplified by induction of ABF-1 in primary immunization, suggesting ABF-1 may play a pivotal role in promoting germinal center B cells to become memory B cells.
In summary, we demonstrated that Blimp-1-mediated ABF-1 repression was required for plasmacytic differentiation in vitro and in vivo. Thus, the regulatory axis of Blimp-1 and ABF-1 may decide the fate of activated B cells to become either plasma cells or memory B cells.

Contents

Chapter 1
Introduction 1
1.1 HLH proteins and B lymphocyte development 1
1.2 ABF-1, a transcriptional repressor in activated human B
cells 2
1.3 Priming of B cells 3
1.4 GC reaction
4
1.5 Memory B cell and antigen recall response 6
1.6 Blimp-1, a master regulator of plasma cell
differentiation 6
1.7 Repression of mature B cell genes by Blimp-1 in plasma
cell differentiation 9
1.8 Specific aim 9

Chapter 2 Materials and Methods 11
2.1 Cell culture and reagents 11
2.2 Plasmid 12
2.3 Generation of EμVH-ABF-1-estrogen receptor transgenic mice 12
2.4 Immunization, BrdU labeling and adoptive transfer study
13
2.5 Generation of lentivirus and viral transduction 14
2.6 RNA isolation and RT-quantitative PCR (RT-QPCR) 14
2.7 Immunoblotting 15
2.8 Chromatin immunoprecipitation (ChIP) 15
2.9 DNA pull-down assay and EMSA 16
2.10 Transfection and luciferase reporter assay 16
2.11 ELISA and ELISPOT assays 18
2.12 Propidium iodide (PI) staining 18
2.13 Apoptotic assay 19
2.14 Flow cytometry 19
2.15 Immunohistochemistry 20
2.16 Microarray 20

Chapter 3 Results 22
3.1 ABF-1 is expressed in human memory B cell and activated B cells but is repressed in plasma cells 22
3.2 Ectopic expression of ABF-1 in B cells inhibits the differentiation of antibody secreting plasma cells 22
3.3 Knockdown of ABF-1 by shRNA enhances plasma cell differentiation 23
3.4 ABF-1 arrests B cell expansion 24
3.5 ABF-1 regulates genes in transcription network of plasma cell differentiation 24
3.6 Identification of genes in B cells associated with enhanced ABF-1 expression 25
3.7 ABF-1 expression was correlated with cell cycle status and was repressed by Blimp-1 26
3.8 Blimp-1 directly represses ABF-1 26
3.9 Msc, an ortholog of ABF-1 in mice, is expressed in GC B cells, memory B cells and activated B cells in response to T-dependent stimulation 28
3.10 Induction of ABF-1 in primary response enhances GC formation and the generation of antigen specific memory B cells 29
3.11 Induction of ABF-1 repressed plasma cell formation in primary immunization 31
3.12 Induction of ABF-1 during Ag recall blocks plasma cell formation 31
3.13 Secondary immune responses in ABF-1 ITG mice 32

Chapter 4 Discussion 34
4.1 Regulation of plasmacytic differentiation by ABF-1 34
4.2 Blimp-1 directly represses ABF-1 35
4.3 Mechanism of ABF-1 in repressing plasmacytic differentiation 36
4.4 In vivo study of ABF-1’s function 39
4.5 Conclusion 43

Chapter 5 References 45

Figure content

FIGURE 1. Expression of ABF-1 and Blimp-1 in stimulated human peripheral B cells 54
FIGURE 2. Enforced expression of ABF-1 represses IgM secretion 55
FIGURE 3. Enforced expression of ABF-1 represses plasma cell differentiation 56
FIGURE 4. shRNA knockdown ABF-1 assists plasmacytic differentiation 57
FIGURE 5. ABF-1 regulates cell proliferation, but not cell survival 58
FIGURE 6. Identification of ABF-1 downstream genes 59
FIGURE 7. Identification of ABF-1 downstream genes by cDNA microarray 60
FIGURE 8. Expression of ABF-1 is inversely correlated with Blimp-1 expression 61
FIGURE 9. Blimp-1 directly suppresses ABF-1 62
FIGURE 10. Blimp-1 directly suppresses ABF-1 63
FIGURE 11. Msc is induced by TFH-mediated signals 64
FIGURE 12. NF-κB signaling is required for Msc expression
65
FIGURE 13. B cell development and ABF-1-ER expression in ABF-1-ER transgenic mice 66
FIGURE 14. Induction of ABF-1 in vivo alters GC B cell formation 67
FIGURE 15. Induction of ABF-1 in vivo alters memory B cell formation 69
FIGURE 16. Induction of ABF-1 in vivo prevents plasma cell formation 70
FIGURE 17. Induction of ABF-1 doesn’t interfere IgM secretion, CSR and IgG affinity 71
FIGURE 18. Induction of ABF-1 during Ag recall blocks plasma cell formation 72
FIGURE 19. Memory B cells of ITG mice induced more antibody-secreting plasma cells 73
FIGURE 20. Proposed model of the functions of ABF-1 in determining plasma cell and memory B cell differentiation
74

Table content

Table I. Genes that are down-regulated by more than 2-fold in SKW B cells that overexpress ABF-1 75
Table II. Genes that are up-regulated by more than 2-fold in SKW B cells that overexpress ABF-1 76

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