近期,，南開大學(xué)生命科學(xué)學(xué)院尹芝南教授實(shí)驗(yàn)組關(guān)于γδ T細(xì)胞分別在腫瘤和肝炎中的功能的兩份研究成果被Journal of Immunology（JI）接收,。這兩篇文章的第一作者均為2009級(jí)博士研究生郝健磊。此前,，他于2010年在JI上以共同第一作者身份已發(fā)表論文1篇,。2011年7月，他榮獲南開大學(xué)“優(yōu)博培育”資助,。
這3篇研究工作分別探討的是小鼠γδ T細(xì)胞在腫瘤和肝炎中的調(diào)控作用,。γδ T細(xì)胞是一群獨(dú)特的免疫細(xì)胞，外周主要由Vg1和Vg4兩個(gè)亞群組成,。郝健磊2010年發(fā)表的工作表明,，Vg4細(xì)胞是天然的能夠直接殺傷腫瘤的γδ T細(xì)胞，其機(jī)制是能夠直接識(shí)別腫瘤細(xì)胞并表達(dá)高水平的殺傷因子,。近期的研究表明,，在腫瘤中，Vg1細(xì)胞起到抑制腫瘤免疫的作用,，清除Vg1細(xì)胞就可以有效地預(yù)防腫瘤,，而Vg1細(xì)胞抑制的靶點(diǎn)恰恰是Vg4細(xì)胞的殺傷功能；有趣的是,，在肝炎中,，Vg4細(xì)胞起到很強(qiáng)的負(fù)調(diào)控作用，輸入Vg4細(xì)胞可以很好地治療肝損傷,。最近的這兩份工作在9月份剛剛被JI接收,。
JI為美國(guó)免疫學(xué)家協(xié)會(huì)（AAI）主辦的刊物，1916年創(chuàng)刊以來(lái)一直是免疫學(xué)界最權(quán)威的雜志之一,。
γδ T細(xì)胞是適應(yīng)性免疫系統(tǒng)的重要成員T細(xì)胞的一大亞類,，由于其表面的TCR是由γ和δ鏈組成而命名。相對(duì)于αβT細(xì)胞而言,，γδT細(xì)胞有許多特殊的天然免疫系統(tǒng)特性：γδTCR具有高度多樣性,、不具M(jìn)HC限制性和不依賴抗原的處理和呈遞過程，表明γδT細(xì)胞在抗感染中起第一線的防御作用,；γδT細(xì)胞可以不依賴于胸腺的發(fā)育,，在體內(nèi)某些組織擁有優(yōu)勢(shì)分布，既有細(xì)胞毒活性,，又能分泌各種細(xì)胞因子,，被稱作固有免疫與適應(yīng)性免疫的橋梁細(xì)胞；γδT細(xì)胞能調(diào)控免疫反應(yīng)且具有毒殺多種癌細(xì)胞與被病毒感染的細(xì)胞的能力,，但其對(duì)抗原的識(shí)別與αβT細(xì)胞并不相似,，在歷經(jīng)長(zhǎng)期進(jìn)化后，相比αβT細(xì)胞,，γδT細(xì)胞以更廣泛,、快速和直接的方式對(duì)體內(nèi)應(yīng)激事件作出反應(yīng)。外周的γδ T細(xì)胞主要由Vγ1和Vγ4兩個(gè)亞群組成,，兩群γδ T細(xì)胞在多種免疫應(yīng)答中具有不同的調(diào)控作用,。
由于γδT細(xì)胞抗原識(shí)別的多樣性和機(jī)制的復(fù)雜性等原因，目前對(duì)γδ T細(xì)胞作用機(jī)制的認(rèn)識(shí)遠(yuǎn)遠(yuǎn)滯后于γδ T細(xì)胞,。深入探討γδ T細(xì)胞亞群的作用機(jī)制,，是免疫學(xué)基礎(chǔ)研究的核心問題和研究前沿之一。
尹芝南教授多年來(lái)致力于γδ T細(xì)胞作用機(jī)制的研究,，在國(guó)家杰出青年科學(xué)基金及國(guó)家973項(xiàng)目等資助下,，其課題組針對(duì)γδ T細(xì)胞亞群在腫瘤和炎癥中的不同作用機(jī)制開展研究， 2010年他們發(fā)現(xiàn)Vγ4細(xì)胞是天然的能夠直接殺傷腫瘤的γδ T細(xì)胞亞群,，其機(jī)制是通過TCR和NKG2D直接識(shí)別黑色素瘤等腫瘤細(xì)胞并表達(dá)高水平的殺傷因子IFN-γ和Perforin（JI 2010）,。
以此為基礎(chǔ)，最近他們的研究發(fā)現(xiàn),，在腫瘤中Vγ1細(xì)胞起到抑制腫瘤免疫的作用,，而Vγ1細(xì)胞抑制的靶點(diǎn)恰恰是Vγ4細(xì)胞對(duì)腫瘤的殺傷功能（JI 2011）,。他們的研究還表明，與抗腫瘤機(jī)制不同的是,，γδ T細(xì)胞在Con A誘導(dǎo)的肝損傷中起到很強(qiáng)的免疫負(fù)調(diào)作用,，Vγ4細(xì)胞通過分泌細(xì)胞因子IL-17發(fā)揮負(fù)調(diào)作用，IL-17抑制NKT細(xì)胞的IFN-γ產(chǎn)生,，從而緩解肝損傷（JI 2011）,。（生物谷Bioon.com）
doi:10.4049/jimmunol.1101389
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Regulatory Role of Vγ1 γδ T Cells in Tumor Immunity through IL-4 Production
Jianlei Hao, Siyuan Dong, Siyuan Xia, Weifeng He, Hao Jia, Song Zhang, Jun Wei, Rebecca L. O’Brien, Willi K. Born, Zhenzhou Wu, Puyue Wang, Jihong Han, Zhangyong Hong,Liqing Zhao and Zhinan Yin*
It has been demonstrated that the two main subsets of peripheral γδ T cells, Vγ1 and Vγ4, have divergent functions in many diseases models. Recently, we reported that Vγ4 γδ T cells played a protective role in tumor immunity through eomesodermin-controlled mechanisms. However, the precise roles of Vγ1 γδ T cells in tumor immunity, especially whether Vγ1 γδ T cells have any interaction with Vγ4 γδ T cells, remain unknown. We demonstrated in this paper that Vγ1 γδ T cells suppressed Vγ4 γδ T cell-mediated antitumor function both in vitro and in vivo, and this suppression was cell contact independent. Using neutralizing anti–IL-4 Ab or IL-4−/− mice, we determined the suppressive factor derived from Vγ1 γδ T cells was IL-4. Indeed, treatment of Vγ4 γδ T cells with rIL-4 significantly reduced expression levels of NKG2D, perforin, and IFN-γ. Finally, Vγ1 γδ T cells produced more IL-4 and expressed significantly higher level of GATA-3 upon Th2 priming in comparison with Vγ4 γδ T cells. Therefore, to our knowledge, our results established for the first time a negative regulatory role of Vγ1 γδ T cells in Vγ4 γδ T cell-mediated antitumor immunity through cell contact-independent and IL-4–mediated mechanisms. Selective depletion of this suppressive subset of γδ T cells may be beneficial for tumor immune therapy.
doi:10.4049/jimmunol.1101315
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Vγ4 γδ T Cell-Derived IL-17A Negatively Regulates NKT Cell Function in Con A-Induced Fulminant Hepatitis
Na Zhao Jianlei Hao Yuanyuan Ni Wei Luo Ruifang Liang Guangchao Cao Yapu Zhao Puyue Wang Liqing Zhao Zhigang Tian Richard Flavell Zhangyong Hong Jihong Han Zhi Yao Zhenzhou Wu and Zhiyan Yin *
Con A-induced fulminant hepatitis is a well-known animal model for acute liver failure. However, the role of γδ T cells in this model is undefined. In this report, using TCR δ−/− mice, we demonstrated a protective role of γδ T cells in Con A-induced hepatitis model. TCR δ−/− mice showed significantly decreased levels of IL-17A and IL-17F in the Con A-treated liver tissue, and reconstitution of TCR δ−/− mice with wild-type (Wt), but not IL-17A−/−, γδ T cells significantly reduced hepatitis, strongly suggesting a critical role of IL-17A in mediating the protective effect of γδ T cells. Interestingly, only Vγ4, but not Vγ1, γδ T cells exerted such a protective effect. Furthermore, depletion of NKT cells in TCR δ−/− mice completely abolished hepatitis, and NKT cells from Con A-challenged liver tissues of TCR δ−/− mice expressed significantly higher amounts of proinflammatory cytokine IFN-γ than those from Wt mice, indicating that γδ T cells protected hepatitis through targeting NKT cells. Finally, abnormal capacity of IFN-γ production by NKT cells of TCR δ−/− mice could only be downregulated by transferring Wt, but not IL-17−/−, Vγ4 γδ T cells, confirming an essential role of Vγ4-derived IL-17A in regulating the function of NKT cells. In summary, our report thus demonstrated a novel function of Vγ4 γδ T cells in mediating a protective effect against Con A-induced fulminant hepatitis through negatively regulating function of NKT cells in an IL-17A–dependent manner, and transferring Vγ4 γδ T cells may provide a novel therapeutic approach for this devastating liver disease.
