Galectin-3在Th17 細胞分化中所扮演的角色

The Role of Galectin-3 in Th17 Differentiation

朱安翔(An-Hsiang Chu)

指導教授 ： 繆希椿

國立臺灣大學/醫學院/免疫學研究所/碩士(2009年)

https://doi.org/10.6342/NTU.2009.00963

摘要

第十七型輔助型T細胞 (T helper 17 cells, Th17 cells)，一個最近被大量研究的輔助型T細胞分支，在病理上被認為是導致自體免疫疾病的主要原因之一。在Th17的細胞分化以及生理作用上,之前研究中已提供許多方面深入的探討。然而在Th17細胞之負向調控機制上，則相對的較缺乏清楚的了解並且仍需要更多的研究。
在此研究中我們發現，與野生控制組相比，Galectin-3基因剔除之輔助型T細胞於體外分化時較容易且大量的分化至Th17細胞，伴隨著主要分泌之細胞激素( IL-17, IL-21 )以及其它Th17細胞相關分子( RORγt , RORα and IL-23R )表現量顯著的升高，暗示Galectin-3或許具有負向調控Th17細胞分化之效應。利用攜帶Galectin-3之逆轉錄病毒感染分化中的第十七型輔助型T細胞，我們發現以此方法過度表現Galectin-3的確能夠減少Galectin-3基因剔除之Th17細胞族群，更進一步的證實Galectin-3在Th17分化中所扮演的負向角色。另外藉由冷光酵素酶分析，我們發現Galectin-3能夠抑制Il21基因啟動子之活性。由於IL-21為Th17分化過程所必需以促進自身生長的細胞激素，這有可能即是Galectin-3負向調控Th17 細胞分化中所運用的機制之一。根據以上的研究結果，我們推測的結論為Galectin-3分子在Th17細胞分化過程中扮演一個負面調控的角色。

關鍵字

Galectin ； Th17

並列摘要

T helper 17, a recently discovered subset in the effector arm of T helper cells and also a major contributor to autoimmune diseases, has been the subject of intense research. To date, a great amount of information on the lineage differentiation and functions of Th17 has been generated. In contrast, only few molecules that are involved in the negative control of Th17 cells have been identified and therefore the negative regulatory mechanisms on Th17 lineage development remain largely elusive.
In this study, we found that Galectin-3-deficient Th cells differentiated more efficiently to the Th17 lineage than wild type Th cells. The gene expression level of major cytokine products such as IL-17 and IL-21 along with several lineage-associated markers, including RORγt, RORα and IL-23R, was correspondingly enhanced in Galectin-3 KO Th17 cells. Overexpression of retroviral Galectin-3 in differentiating Th17 cells slightly decreased the IL-17 production in Galectin-3-deficient cells, demonstrating its negative regulatory role in the Th17 differentiation. In addition, in vitro promoter luciferase assay revealed a potential role of Galectin-3 to suppress the transcription of Il21, the major self-amplifying cytokines during the early differentiation of Th17 cell lineage, thus providing a reasonable mechanism underlying the negative regulation by Galectin-3. Based on above observations, we conclude that Galectin-3 play a negative role in the differentiation of Th17 cells.

並列關鍵字

Galectin ； Th17

參考文獻

Acosta-Rodriguez, E. V., Montes, C. L., Motran, C. C., Zuniga, E. I., Liu, F.-T., Rabinovich, G. A., and Gruppi, A. (2004). Galectin-3 Mediates IL-4-Induced Survival and Differentiation of B Cells: Functional Cross-Talk and Implications during Trypanosoma cruzi Infection. J Immunol 172, 493-502.

Aggarwal, S., Ghilardi, N., Xie, M.-H., de Sauvage, F. J., and Gurney, A. L. (2003). Interleukin-23 Promotes a Distinct CD4 T Cell Activation State Characterized by the Production of Interleukin-17. J Biol Chem 278, 1910-1914.

Ahmad, N., Gabius, H.-J., Andre, S., Kaltner, H., Sabesan, S., Roy, R., Liu, B., Macaluso, F., and Brewer, C. F. (2004). Galectin-3 Precipitates as a Pentamer with Synthetic Multivalent Carbohydrates and Forms Heterogeneous Cross-linked Complexes. J Biol Chem 279, 10841-10847.

Batten, M., Li, J., Yi, S., Kljavin, N. M., Danilenko, D. M., Lucas, S., Lee, J., de Sauvage, F. J., and Ghilardi, N. (2006). Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat Immunol 7, 929-936.

Bauquet, A. T., Jin, H., Paterson, A. M., Mitsdoerffer, M., Ho, I. C., Sharpe, A. H., and Kuchroo, V. K. (2009). The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nat Immunol 10, 167-175.