近期，南开大学生命科学学院尹芝南教授实验组关于γδ T细胞分别在肿瘤和肝炎中的功能的两份研究成果被Journal of Immunology（JI）接收。这两篇文章的第一作者均为2009级博士研究生郝健磊。此前，他于2010年在JI上以共同第一作者身份已发表论文1篇。2011年7月，他荣获南开大学“优博培育”资助。
这3篇研究工作分别探讨的是小鼠γδ T细胞在肿瘤和肝炎中的调控作用。γδ T细胞是一群独特的免疫细胞，外周主要由Vg1和Vg4两个亚群组成。郝健磊2010年发表的工作表明，Vg4细胞是天然的能够直接杀伤肿瘤的γδ T细胞，其机制是能够直接识别肿瘤细胞并表达高水平的杀伤因子。近期的研究表明，在肿瘤中，Vg1细胞起到抑制肿瘤免疫的作用，清除Vg1细胞就可以有效地预防肿瘤，而Vg1细胞抑制的靶点恰恰是Vg4细胞的杀伤功能；有趣的是，在肝炎中，Vg4细胞起到很强的负调控作用，输入Vg4细胞可以很好地治疗肝损伤。最近的这两份工作在9月份刚刚被JI接收。
JI为美国免疫学家协会（AAI）主办的刊物，1916年创刊以来一直是免疫学界最权威的杂志之一。
γδ T细胞是适应性免疫系统的重要成员T细胞的一大亚类，由于其表面的TCR是由γ和δ链组成而命名。相对于αβT细胞而言，γδT细胞有许多特殊的天然免疫系统特性：γδTCR具有高度多样性、不具MHC限制性和不依赖抗原的处理和呈递过程，表明γδT细胞在抗感染中起第一线的防御作用；γδT细胞可以不依赖于胸腺的发育，在体内某些组织拥有优势分布，既有细胞毒活性，又能分泌各种细胞因子，被称作固有免疫与适应性免疫的桥梁细胞；γδT细胞能调控免疫反应且具有毒杀多种癌细胞与被病毒感染的细胞的能力，但其对抗原的识别与αβT细胞并不相似，在历经长期进化后，相比αβT细胞，γδT细胞以更广泛、快速和直接的方式对体内应激事件作出反应。外周的γδ T细胞主要由Vγ1和Vγ4两个亚群组成，两群γδ T细胞在多种免疫应答中具有不同的调控作用。
由于γδT细胞抗原识别的多样性和机制的复杂性等原因，目前对γδ T细胞作用机制的认识远远滞后于γδ T细胞。深入探讨γδ T细胞亚群的作用机制，是免疫学基础研究的核心问题和研究前沿之一。
尹芝南教授多年来致力于γδ T细胞作用机制的研究，在国家杰出青年科学基金及国家973项目等资助下，其课题组针对γδ T细胞亚群在肿瘤和炎症中的不同作用机制开展研究， 2010年他们发现Vγ4细胞是天然的能够直接杀伤肿瘤的γδ T细胞亚群，其机制是通过TCR和NKG2D直接识别黑色素瘤等肿瘤细胞并表达高水平的杀伤因子IFN-γ和Perforin（JI 2010）。
以此为基础，最近他们的研究发现，在肿瘤中Vγ1细胞起到抑制肿瘤免疫的作用，而Vγ1细胞抑制的靶点恰恰是Vγ4细胞对肿瘤的杀伤功能（JI 2011）。他们的研究还表明，与抗肿瘤机制不同的是，γδ T细胞在Con A诱导的肝损伤中起到很强的免疫负调作用，Vγ4细胞通过分泌细胞因子IL-17发挥负调作用，IL-17抑制NKT细胞的IFN-γ产生，从而缓解肝损伤（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.
