探討c-Maf在不變自然殺手T細胞之細胞激素基因表現中所扮演的角色

c-Maf屬於large Maf家族轉錄因子的一員，其對於第二型、第十七型、濾泡型輔助T細胞以及第一型調節性T細胞之細胞激素產生與分化過程的調節扮演重要的角色。不變自然殺手T細胞在接受其專一性醣脂質抗原-galactosylceramide (-GalCer) 的刺激後能快速地產生輔助型T細胞相關之細胞激素，例如：干擾素-、介白素-4及介白素-17。然而c-Maf在不變自然殺手T細胞及其所調節的疾病中所扮演的角色仍然是未知的。在本研究中，我們證實不變自然殺手T細胞在經由-GalCer刺激後會表現c-Maf轉錄本及蛋白。利用c-Maf缺失之胎鼠肝細胞重建小鼠進一步證明c-Maf缺失之不變自然殺手T細胞，相較於野生型不變自然殺手T細胞，在接收-GalCer刺激後會產生較少量的介白素-17A。雖然c-Maf基因缺失不會影響不變自然殺手T細胞的發育過程與活化狀態，但c-Maf對於不變自然殺手T細胞受到微環境中的介白素-6、介白素-1以及轉化生長因子- 誘導成第十七型不變自然殺手T細胞的過程以及RORt的最佳表現量是不可缺的。因此，c-Maf缺失之第十七型不變自然殺手T細胞失去其吸引嗜中性球遷移到肺臟的能力。總結來說，c-Maf在第十七型不變自然殺手T細胞中對於介白素-17A及RORt的表現扮演了正向調節的角色。對於由第十七型不變自然殺手T細胞所調節的發炎疾病，提供了一個具有潛力的治療目標。

關鍵字

不變自然殺手T細胞； c-Maf ；介白素-17 ；細胞激素調控；呼吸道嗜中性球增多

並列摘要

c-Maf belongs to the large Maf family of transcription factors and plays a key role in the regulation of cytokine production and differentiation of TH2, TH17, TFH and Tr1 cells. Invariant natural killer T (iNKT) cells can rapidly produce large quantity of TH-related cytokines such as IFN-, IL-4 and IL-17A upon stimulation by glycolipid antigens, such as -galactosylceramide (-GalCer). However, the role of c-Maf in iNKT cells and iNKT cells-mediated diseases remains poorly understood. In this study, we demonstrate that -GalCer-stimulated iNKT cells express c-Maf transcript and protein. By using c-Maf-deficient fetal liver cell-reconstituted mice, we further show that c-Maf-deficient iNKT cells produce less IL-17A than their wild-type (WT) counterparts after -GalCer stimulation. While c-Maf deficiency does not affect the development and activation of iNKT cells, c-Maf is essential for the induction of IL-17-producing iNKT (iNKT17) cells by IL-6, TGF- and IL-1, and the optimal expression of RORt. Therefore, c-Maf-deficient iNKT17 cells lose the ability to recruit neutrophils into the lungs. Taken together, c-Maf is a positive regulator for the expression of IL-17A and RORt in iNKT17 cells. It is a potential therapeutic target in iNKT17 cell-mediated inflammatory disease.

並列關鍵字

invariant natural killer T cells ； c-Maf ； IL-17 ； cytokine regulation ； airway neutrophilia

參考文獻

Akabari, O., Stock, P., Meyer, E., Kronenberg, M., Sidobre, S., Nakayama, T., Taniguchi, M., Grusby, M.J., DeKruyff, R.H., and Umetsu, D.T. (2003). Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. Nat. Med. 9, 582-588.

Akbari, O., Faul, J.L., Hoyte, E.G., Berry, G.J., Wahlstrom, J., Kronenberg, M. et al. (2006). CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma. N. Engl. J. Med. 354, 1117-1129.

Andris, F., Denanglaire, S., Anciaux, M., Hercor, M., Hussein, H., and Leo, O. (2017). The transcription factor c-Maf promotes the differentiation of follicular helper T cells. Front. Immunol. 8, 480-490.

Apetoh, L., Quintana, F.J., Pot, C., Joller, N., Xiao, S., Kumar, D., Burns, E.J., Sherr, D.H., Weiner, H.L., and Kuchroo, V.K. (2010). The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat. Immunol. 11, 854-861.

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.

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探討c-Maf在不變自然殺手T細胞之細胞激素基因表現中所扮演的角色

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