臺灣博碩士論文加值系統

Galectin-3，為分子量31 kDa的蛋白質，是屬於beta-galectose-binding lectin家族的一員，能正向與負向地調節T細胞和巨噬細胞的免疫功能。Galectin-3主要分布於細胞質內，然而近期研究也在細胞核、細胞表面以及細胞外間質偵測到Galectin-3的表現，暗示此分子為多功能性蛋白質。目前有越來越多的研究證據指出Galectin-3會參與調節T細胞免疫功能和細胞凋亡。Galectin-3能正向和負向地調節T細胞反應，但是Galectin-3在T細胞活化和凋亡方面的角色仍舊不是很清楚。為了要研究Galectin-3對T細胞的作用，首先，我們分離人類T細胞，進一步去研究Galectin-3對T細胞活化的影響。我們證實當T細胞藉由anti-CD3抗體活化之後其Galectin-3的表現量會提高，而此增加表現的趨勢在核酸和蛋白質階層下都能觀察到。利用anti-CD3抗體引發T細胞活化的同時加入Galectin-3，能造成T細胞增生並引起細胞激素IFNγ和IL-4的分泌。自Galectin-3基因敲毀小鼠所分離出的splenocytes對anti-CD3抗體所產生的活化反應較差，而此缺失能藉由外加Galectin-3所修復。以上實驗指出Galectin-3具有調節T細胞活化之功能。Galectin-3除了能增強T細胞活化之外，外源性的Galectin-3也能引發細胞凋亡。為了進一步去探討Galectin-3在人類T細胞所引發的細胞凋亡，我們分離人類T細胞，進而去研究在不同的活化狀態之下以及不同的T細胞亞群之間對Galectin-3所引發的細胞凋亡的反應。我們的結果發現，活化狀態下的T細胞對Galectin-3所引發的細胞凋亡較靜止狀態下的T細胞表現比較高的抗性，暗指T細胞對Galectin-3所引發的細胞凋亡受活化狀態所調控。另外我們也證明CD8 T細胞比CD4 T細胞對Galectin-3所引發的細胞凋亡表現比較高的敏感性，而在CD45RA和CD45RO T細胞亞群之間沒有顯著差異，暗示naïve和memory T細胞對Galectin-3所引發的細胞凋亡感受性沒有差異。而Galectin-3所引發的細胞凋亡能藉由外加caspase 抑制劑所抑制。綜合實驗結果顯示Galectin-3的確在調節T細胞活化跟凋亡方面有重要的角色。

Galectin-3, a 31 kDa protein, belonging to the member of a growing family of beta – galactoside - binding lectin, positively and negatively regulates T cell immunity and macrophage function. Although Galectin-3 is predominantly located in the cytoplasm, it has also been detected in the nucleus, on the cell surface or in the extracellular environment, suggesting a multi-functionality of this molecule. There is growing evidence showing the involvement of galectin-3 in the regulation of T cell immune response and apoptosis. Galetin-3 can positively and negatively regulate T cell response. Role of galectin-3 in T cell activation and apoptosis is still not clear. In order to investigate the effects of galectin-3 in T cells, we isolated human T cells to study T cell activation in vitro. We demonstrated that the expression of galectin-3 is upregulated in primary human T cells when cells activated with anti-CD3 mAb in both real-time PCR and intracellular galectin-3 staining. The exposure of exogenous galectin-3 to primary human T cells enhanced proliferation response to immobilized anti-CD3. We further demonstrated that exogenous galectin-3 induced IFN-γ production during T cell activation. The splenocytes isolated from galectin-3 deficient mice impaired proliferation response to anti-CD3 and this defect can be restored by adding recombinant galectin-3, indicating that galectin-3 may play a role in T cell activation. In addition to induce T cell activation, exogenous galectin-3 is also able to induce apoptosis in resting T cells. For investigating role of galectin-3-induced apoptosis in human T cells, we isolated primary human T cells and study the response to exogenous galectin-3 in different activation states and T cell subsets. The results revealed that activated T cells were more resistant to galecin-3-induced apoptosis than resting T cells indicating that galectin-3-induced apoptosis is under regulation, depending on T cell activation states. We also demonstrated that CD8 T cells were more sensitive to galectin-3-induced apoptosis than CD4 T cells and there was no significant difference between CD45RO and CD45RA T cell subsets in galectin-3-induced cell apoptosis indicating that no significant difference between naïve and primary T cell subsets. Galectin-3-induced apoptosis could be inhibited by caspase inhibitors. In conclusion, these results suggest that galectin-3 may play an important role in T cell activation and apoptosis.

Abstract 2
中文摘要 4

Chapter Ⅰ. Introduction
Part Ⅰ. Structural characteristics of galectin-3 9
Part Ⅱ. Cell distribution of galectin-3 10
Part Ⅲ. Biological function of galectin-3 11
Part Ⅳ. Galecin-3 in immune response 12

Chapter Ⅱ. Aims of the study
Part Ⅰ. Involvement of galectin-3 in T cell activation 14
Part Ⅱ. Involvement of galectin-3 in T cell apoptosis 14

Chapter Ⅲ. Materials and Methods
Part Ⅰ. Materials
1. Cell Lines 16
2. Antibodies 16
3. Chemicals and reagents 16
4. Buffers 18
Part Ⅱ. Method
1. Galectin genes mRNA expression analysis by real-time PCR 18
2. Flow cytometry analysis
2.1 Surface marker staining 19
2.2 Intracellular galectin-3 staining 19
2.3 Annexin V staining 20
3. Human T cells analysis
3.1 Isolation of human T cells 20
3.2 Human T cells proliferation assay 20
4. Apoptosis assay 21
5. Cytokine production on human T cells 21

Chapter IV. Results
Part Ⅰ. After T cell activation, the mRNA level of Gal-1, Gal-3, Gal-9 is
upregulated 22
Part Ⅱ. Intracellular Galectin-3 is expressed in human resting T cell and
upregulated after T cell activation 22
Part Ⅲ. The absence of Galectin-3 decreases cell proliferation 23
Part Ⅳ. Stimulation of T cells by recombinant Galectin-3 23
Part Ⅴ. Galectin-3 induces T cell apoptosis 25

Chapter Ⅴ. Discussions
Part Ⅰ. The expression of galectin-3 was upregulated after T cell activation 27
Part Ⅱ. Adding exogenous galectin-3 in vitro enhances cell proliferation 28
Part Ⅲ. Galectin-3 induced cell apoptosis 30
Part Ⅳ. Conclusion 32

Reference 33

Figures
Figure 1. Expression of galectin family genes after T cell activation 41
Figure 2. Expression of surface and intracellular galectin-3 after T cell activation 42
Figure 3. Expression and purification of His-Tag galectin-3 protein 44
Figure 4. Impaired T cell proliferation to anti-CD3 Ab in galectin-3 deficient
cell 45
Figure 5. Exogenous recombinant galectin-3 could enhance T cell proliferation to
anti-CD3 47
Figure 6. Exogenous galectin-3 enhances IFNγ secretion by human T cells 48
Figure 7. Exogenous galectin-3 enhances IL-4 secretion by human T cells 49
Figure 8. Exogenous galectin-3 induces apoptosis in human Jurkat T cells 50
Figure 9. Human T cells were resistant to galectin-3-induced apoptosis after
activation by anti-CD3 mAb 51
Figure 10. CD8 T cells are more susceptible to exogenous galectin-3-induced
apoptosis 53
Figure 11. Galectin-3-incuced apoptosis was partially inhibited by pan-caspase inhibitor, z-VAD-fmk 55

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