武大校友最新《自然》文章解析免疫学突破性进展

　　生物通报道：来自美国MD安德森癌症研究中心免疫学系，美国国立健康研究院NIH系统生物学研究院等处的研究人员发现了不同于CD4⁺辅助T细胞T_H1和T_H2亚组的一种截然不同的亚组：T_HIL-17，并且进一步研究发现在小鼠T_H17细胞中能高度表达IL-21，从而认为IL-21是一种在TH17分化过程中必需和必要的自分泌细胞因子（autocrine cytokine），可以作为治疗炎症疾病的一种潜在靶标。这一研究成果公布在《Nature》杂志上

文章的通讯作者之一是美国MD安德森癌症研究中心免疫学系的分子免疫学与免疫调节专家董晨副教授，其于1989年在武汉大学获得学士学位，之后赴美留学，目前任职安德鲁癌症中心免疫学系。

原文摘要：
Nature 448, 480-483 (26 July 2007) | 
doi:10.1038/nature05969; Received 7 March 2007; Accepted 4 June 2007; Published online 20 June 2007
Essential autocrine regulation by IL-21 in the generation of inflammatory T cells
[Abstract]

T细胞在胸腺中成熟，获得其功能及学习识别自我。胸腺完成阳性选择(让识别抗原/MHC的克隆增殖，成熟并移行至周围)和阴性选择(排除能将自身抗原作为异物起反应的克隆)的双重功能。有关这种选择确切的细胞和分子机制还未完全阐明。

从骨髓衍生的T-干细胞在胚胎发育过程移行至胸腺，在胸腺经历了成熟和学习识别自我，经胸腺的选择，成熟的淋巴细胞才被准许离开胸腺，可见于外周血和淋巴样组织中，所有成熟的T细胞仅表达CD4或CD8中的一种。

通常将表达CD4的T细胞归属于辅助T细胞（helper T cell，T_H）。辅助T细胞在免疫反应中扮演中间过程的角色：它可以增生扩散来激活其它类型的产生直接免疫反应的免疫细胞，主要表面标志是CD4。 T细胞调控或“辅助”其它淋巴细胞发挥功能。

这些细胞可根据它们的功能，对不同细胞因子的应答以及分泌细胞因子的能力可再分成两个主要部分。现认为T_H细胞起始于能分泌IL-2的前身细胞，经最初的刺激，这些细胞发育为THO细胞，它能分泌几种细胞因子，包括IFN-γ,IL-2,IL-4,IL-5和IL-10。根据细胞因子的作用，T_HO细胞能发育成为T_H1或T_H2细胞。IFN-γ和IL-12有利于TH1的发育，而IL-4和IL-10有利于T_H2的发育。T_H1细胞分泌IFN-γ，T_H2分泌IL-4，然而这两种亚类均等地分泌其他几种细胞因子(如IL-3,GM-CSF,TNF-α)。一般地说，T_H1有利增强细胞免疫，而T_H2有利于增强体液免疫.

所提到的T_H1和T_H2应答已改变了有关免疫系统与疾病关系的看法。一种免疫应答不仅应有活力，对感染或疾病还需适度。最好的例子是麻风，现相信TH1应答导致结核样麻风，而T_H2应答引起瘤型麻风。再则，T_H1应答可加重自身免疫病，而T_H2应答有利于IgE的分泌和特应性疾病的发展。

总而言之，CD4⁺辅助T细胞经过激活可以分化成不同的亚群效应因子，有各自不同的细胞因子表达和免疫调控功能。在这个分化过程中，T_H1和T_H2细胞分别会产生干扰素，以及白介素4（interleukin (IL)-4）。

董晨研究小组发现了一个截然不同的T_H亚组：T_HIL-17, T_H17 或inflammatory T_H (THi)在介导组织炎症方面是一个不同的TH群。T_H的分离最初是由β转移生长因子（transforming growth factor—β），IL-6启动的，并得到IL-23的正调控。在这个过程中，转录信号转导子与激活子(Signal Transducers and Activators of Transcription，STATs)和视黄醇类核内受体（retinoic acid receptor-related orphan receptor-γ，Ror-γ）介导了分化。T_H17这种特殊的辅助T细胞会分泌IL-17, IL-17F和IL-22，这些都调控了组织细胞炎症反应，但是对于T_H17分化并不起重要作用。

在这篇文章中，研究人员发现在小鼠T_H17细胞中IL-21能高度表达，这是由活化的T细胞IL-6诱导产生的，这个过程依赖于STAT3，但不依赖于Ror-γ。研究人员也发现IL-21潜在引起TH17分化，抑制Foxp3的表达，而这需要STAT3和Ror-γ。同时IL-21缺陷型则会影响TH17细胞传代，导致针对实验性自体免疫脑脊髓炎（autoimmune encephalomyelitis）的保护。因此研究人员认为IL-21是一种在TH17分化过程中必需和必要的自分泌细胞因子（autocrine cytokine），可以作为治疗炎症疾病的一种潜在靶标。
（生物通：万纹）

附:
Chen Dong , Ph.D.

教育经历：
1989年 武汉大学 细胞生物学
1996年 阿拉巴马州大学细胞与分子生物学
1997年-2000年 耶鲁大学免疫学
2000-至今 M. D.安德鲁癌症中心免疫学系

研究兴趣：
The immune system, consisting of innate and adaptive components, functions to identify invading foreign organisms and efficiently eliminate them. T lymphocytes are essential regulators and effectors in immune and autoimmune responses. They are activated by antigen-presenting cells (APC), dendritic cells (DC) in particular, in secondary lymphoid organs. After activation, CD4+ helper T (Th) cells differentiate into effector subsets that secrete cytokines to regulate different types of immune responses. CD8+ T cells, after activation, differentiate into cytotoxic cells. In addition to their effector function, activated T cells also gain the ability to migrate into non-lymphoid tissues. T cells are normally tolerant to self tissues; however, this self tolerance is lost in autoimmune diseases.

Our research is to understand the molecular mechanisms whereby immune responses are normally regulated, and how abnormal immune regulation leads to immunodeficiency, autoimmunity and allergy disorders. These studies will help us to understand and manipulate the immune system, and to ultimately develop immune therapies for treating autoimmune and allergic diseases, and for eliminating infectious diseases and cancer. 

First, our group is studying the costimulatory factors through which the innate immune system regulates the activation, tolerance and function of T cells. We have discovered and characterized several novel B7/butyrophilin superfamily members that regulate T cell activation and function. In the near future, we will analyze the functional specificity and synergy of these positive and negative costimulators in the context of infection, autoimmune and allergy responses. 

Secondly, we are working to understand the molecular regulation of inflammatory responses. We are studying the function of novel cytokines in the IL-17 family in autoimmunity and allergy. We have identified IL-17-expressing CD4+ T cells as a novel lineage of helper T (TH) cells that regulate tissue inflammation. We are investigating the regulation and function of these cells extensively. 

Thirdly, our group is interested in the signal transduction mechanisms during innate immune responses, with particular interests in dissecting MAP kinase regulation. We are also studying the signaling and transcriptional mechanisms regulating T cell tolerance and effector function. 


近期发表的文章：

Dong, C., Davis, R. J. and Flavell, R. A. MAP kinases and the immune response. (2002) Annual Review of Immunology. 20:80-82.

Nurieva, R., Duong, J., Kishikawa, H., Dianzani, U., Rojo, J. M., Ho, I.-C., Flavell, R. A. and Dong, C. Transcriptional regulation of Th2 differentiation by ICOS. (2003) Immunity. 18:801-811.

Prasad, D. V. R., Richards, S., Mai, X. M., and Dong, C. B7S1, a novel B7 family member that inhibits T cell activation. (2003) Immunity.18:863-873.

Nurieva, R., Mai, X. M., Forbush, K., Bevan, M. J. and Dong, C. B7h is required for T cell activation, differentiation and effector function. (2003) Proceedings of National Academy of Sciences. 100: 14163-14168.

Zhang, Y., Blattman, J., Kennedy, N., Duong, J., Nguyen, T., Wang, Y., Davis, R. J., Greenberg, P., Flavell, R. A. and Dong, C. Regulation of innate and adaptive immune responses by MKP5. (2004) Nature. 430:793-797.

Park, H., Li, Z., Yang, X. O., Chang, S. H., Nurieva, R. I., Wang, Y.-H., Wang, Y., Hood, L., Zhu, Z., Tian, Q., Dong, C. A distinct lineage of TH cells regulates tissue inflammation by producing IL-17. (2005) Nature Immunology. 10: 1133-1142.

Dong, C., Sanjabi, S., and Eynon, E. Gene regulation and function: it’s rocking science. (Meeting Report). (2005) Immunity. 23: 557-560.

Dong, C. Diversification of TH lineages- finding family roots for IL-17. (Perspectives). (2006) Nature Review Immunology. 6:329-333.

Martin-Orozco, N. and Dong, C. New battlefields for costimulation. (Commentaries). (2006) Journal of Experimental Medicine. 203: 817-820.

Nurieva, R.I. Thomas, S., Nguyen, T., Martin-Orozco, N., Wang, Y., Kaja, M.-K., Yu, X.-Z.,and Dong, C. T-cell immunity or tolerance is regulated by a combinatorial costimulation signal. (2006) EMBO Journal. 25: 2623–2633.

Zhang, Y., Chung, Y. S., Bishop, C., Daugherty, B., Chute, H., Holst, P., Kurahara, C., Lott, F., Sun, N., Welcher, A., and Dong, C. Regulation of T cell activation and tolerance by PDL2. (2006) Proceedings of National Academy of Sciences. 103: 11695–11700.

Angkasekwinai, P., Park, H., Wang, Y.-H., Wang, Y.-H., Chang, S. H., Corry, D. B., Liu, Y.-J., Zhu, Z. and Dong, C. IL-25 regulates the initiation of TH2 responses. Journal of Experimental Medicine. In press.

Nurieva, R., Yang, X. O., Martinez, G., Zhang, Y., Panopoulos, A. D., Ma, L., Schluns, K., Tian, Q., Watowich, S. S., Jetten, A. M. and Dong, C. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature. In press.
（更新至2007年6月）