生物通报道：来自南开大学生命科学学院，第三军医大学的研究人员在之前研究的基础上，发表了题为“Regulatory Role of Vγ1 γδ T Cells in Tumor Immunity through IL-4 Production”等两篇文章，介绍了适应性免疫系统重要成员：γδ T细胞的新成果，这两篇文章同期发表在the Journal of Immunology（JI）上。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。

文章的通讯作者是南开大学生命科学学院的尹芝南教授，其早年毕业于湖北医科大学，2007年3月应聘为南开大学生命科学学院院长、博导、****特聘教授，研究组主要研究方向包括，肿瘤免疫的分子机制；gammadelta细胞分化；癌症和自身免疫疾病的免疫学机制和小分子药物筛选。这项研究获得了国家杰出青年科学基金及国家973项目等资助。

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）。

原文摘要：

Regulatory Role of Vγ1 γδ T Cells in Tumor Immunity through IL-4 Production

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.

Vγ4 γδ T Cell-Derived IL-17A Negatively Regulates NKT Cell Function in Con A-Induced Fulminant Hepatitis

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.

作者简介：

尹芝南
性 别：男
职 称：教授
所属部门：微生物学系
招生专业：生物化学与分子生物学
研究方向：1.肿瘤免疫的分子机制；2.gammadelta细胞分化；3.癌症和自身免疫疾病的免疫学机制和小分子药物筛选。

::教师简介::
1997年12月毕业于德国柏林自由大学免疫学专业，获博士学位。
1984年7月毕业于湖北医科大学医疗系获学士学位，1988年8月毕业于上海第二医科大学上海市免疫学研究所。获免疫学硕士。曾为意大利国家肿瘤中心访问学者，1997-2006年历任美国耶鲁大学医学院内科系风湿科博士后、助理研究员、助理教授、副教授和访问副教授。 2007年3月应聘为南开大学生命科学学院院长、博导、****特聘教授、国家杰出青年基金获得者、973项目首席科学家、天津市生物医药创业领军人才。
通讯地址：天津市南开大学生命科学学院，邮编：300071
电话：022-23503270
传真：022-23503270
电子邮件：yinzn@nankai.edu.cn
代表性论文：
1.Chen, L., W.He, S.T.Kim, J.Tao, Y. Gao, H.Chi, A.M.Intlekofer, B.Harvev, S.L.Reiner, Z.Yin*, R.A. Flavell, and J. Craft. Both epigenetic and transcriptional programs contribute to default IFN-g production by gd T cells. J Immunol 2007;178(5):2730-6

2.Tao, J., Y. Gao, M.O.Li, W. He, L. Chen, B.Harvev, R.J.Davis, R.A. Flavell, and Z. Yin*. JNK2 negatively regulates CD8+ T cell effector function and anti-tumor immune response. Eur J Immunol 2007;37:818-829

3. Pandey, V., P. X. Qian, J. Kang, J. K. Perry, M. D. Mitchell, Z. Yin, Z. S. Wu, D. X. Liu, T. Zhu, and P. E. Lobie. Artemin stimulates oncogenicity and invasiveness of human endometrial carcinoma cells. Endocrinology 2010;151:909-920

4.Zhou, X., Z. Yin, X. Guo, D. P. Hajjar, and J. Han. Inhibition of ERK1/2 and activation of liver X receptor synergistically induce macrophage ABCA1 expression and cholesterol efflux. J Biol Chem 2010;285:6316-6326

5.Tang, J. Z., Z. H. Zuo, X. J. Kong, M. Steiner, Z. Yin, J. K. Perry, T. Zhu, D. X. Liu, and P. E. Lobie. Signal transducer and activator of transcription (STAT)-5A and STAT5B differentially regulate human mammary carcinoma cell behavior. Endocrinology 2010;151:43-55

6.Shi, Y., X. F. Liu, Y. Zhuang, J. Y. Zhang, T. Liu, Z. Yin, C. Wu, X. H. Mao, K. R. Jia, F. J. Wang, H. Guo, R. A. Flavell, Z. Zhao, K. Y. Liu, B. Xiao, Y. Guo, W. J. Zhang, W. Y. Zhou, G. Guo, and Q. M. Zou. Helicobacter pylori-induced Th17 responses modulate Th1 cell responses, benefit bacterial growth, and contribute to pathology in mice. J. Immunol. 2010;184:5121-5129.

7. He, W., J. Hao, S. Dong, Y. Gao, J. Tao, H. Chi, R. Flavell, R. O’Brien, W. Born, J. Craft , J. Han, P. Wang, L. Zhao, J. Wu, and Z. Yin*. Naturally Activated Vg4 gd T Cells Play a Protective Role in Tumor Immunity Through Expression of Eomesodermin. J. Immunol. 2010;185:126-133

8.Tang W, Lu Y, Tian QY, Zhang Y, Guo FJ, Liu GY, Syed NM, Lai Y, Lin EA, Kong L, Su J, Yin F, Ding AH, Zanin-Zhorov A, Dustin ML, Tao J, Craft J, Yin Z, Feng JQ, Abramson SB, Yu XP, Liu CJ. The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science. 2011 Apr 22;332(6028):478-84.

9.Hao, J., X. Wu, S. Xia, Z. Li, , T. Wen, N. Zhao, Z.Wu, P.Wang, L.Zhao, Z. Yin*. Current Progress in gd T-Cell Biology. Cell Mol Immunol 2010. 7: 409-413.

10.Hao, J., S. Dong, W. He, H. Jia, S. Zhang, J. Wei, R. O'Brien, W. Born, Z. Wu, P. Wang, L. Zhao, Z. Yin*. Regulatory Role of Vg1 gd T Cells in Tumor Immunity through IL-4 Production. J Immunol 2011. In press.

11.Zhao, N., J. Hao, Y. Ni, W. Luo, P. Wang, L. Zhao, Z. Tian, R. Flavell, Z. Yao, Z. Wu, Z. Yin*. Vg4 gd T Cell-Derived IL-17A Negatively Regulates NKT Cell Function in Con A-Induced Fulminant Hepatitis. J Immunol 2011. In press.

12.Qian, P. X., Z. Zuo, Z. S. Wu, X. Meng, G. Li, Z. Wu, W. Zhang, S. Tan, V. Pandey, Y. Yao, P. Wang, L. Zhao, J. Wang, Q. Wu, E. Song, P. Lobie, Z. Yin*, and T. Zhu. 2011. Pivotal role of reduced let-7g expression in breast cancer invasion and metastasis. Cancer Res 2011. In press.


 

閹垫捁绁�

娑撳娴囩€瑰宓庢导锔炬暩鐎涙劒鍔熼妴濠団偓姘崇箖缂佸棜鍎禒锝堥樋閹活厾銇氶弬鎵畱閼筋垳澧块棃鍓佸仯閵嗗甯扮槐銏狀洤娴ｆ洟鈧俺绻冩禒锝堥樋閸掑棙鐎芥穱鍐箻閹劎娈戦懡顖滃⒖閸欐垹骞囬惍鏃傗敀

10x Genomics閺傛澘鎼isium HD 瀵偓閸氼垰宕熺紒鍡氬劒閸掑棜椴搁悳鍥╂畱閸忋劏娴嗚ぐ鏇犵矋缁屾椽妫块崚鍡樼€介敍锟�

濞嗐垼绻嬫稉瀣祰Twist閵嗗﹣绗夐弬顓炲綁閸栨牜娈慍RISPR缁涙盯鈧鐗哥仦鈧妴瀣暩鐎涙劒鍔�

閸楁洜绮忛懗鐐寸ゴ鎼村繐鍙嗛梻銊ャ亣鐠佹彃鐖� - 濞ｅ崬鍙嗘禍鍡毿掓禒搴ｎ儑娑撯偓娑擃亜宕熺紒鍡氬劒鐎圭偤鐛欑拋鎹愵吀閸掔増鏆熼幑顔垮窛閹貉傜瑢閸欘垵顫嬮崠鏍掗弸锟�

娑撳娴囬妴濠勭矎閼崇偛鍞撮摂瀣鐠愩劋绨版担婊冨瀻閺嬫劖鏌熷▔鏇犳暩鐎涙劒鍔熼妴锟�