专访正教授董晨 开启免疫功能的新通路

【字体: www.ebiotrade.com 时间:2009年08月14日 来源:生物通

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  生物通编者按:8月初,武汉籍德州大学M.D Anderson Cancer Center的董晨教授在《Science》在线版上发表了他一年来的最新研究成果。他带领的研究小组发现了一类新的辅助性T细胞,为免疫学理论体系增添了新内容。

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生物通编者按:2009,已渐行渐远,生命科学的精彩还在继续演绎。一个新的发现可能创造一个全新的研究领域,一个新的发现可能彻底颠覆经典理论,每一位科学家都是生命科学领域的弄潮儿,他或推动着生命科学深刻地变革,或默默填补生命科学认识的鸿沟。2009年,点亮生命之光的是谁?奏响生命之歌的是谁?关注他们,关注赛默飞世尔特约之2009年度生命科学十大风云人物评选!

 

8月初,武汉籍德州大学M.D Anderson Cancer Center的董晨教授在《Science》在线版上发表了他一年来的最新研究成果。他带领的研究小组发现了一类新的辅助性T细胞,为免疫学理论体系增添了新内容。

 

90年本科毕业一年后的董晨踏上了美国之旅,修读博士学位期间师从一位美国院士,也许和院士有缘,在博士后训练阶段他又遇上了一位院士。果然名师出高徒,董晨博士后训练结束后就成为助理教授,之后仅花了8年的时间于40岁成为正教授。这期间,他获得多种奖励,包括今年美国免疫家学会的BD Bioscience学者奖,这是中国免疫学家首次拿到的重大国际奖项。(具体简介见文章后)

 

谈及这段出国的经历,董晨教授表示,他算是幸运的,有今天的成绩。

 

生物通:说说您赴美的经历吧?

 

董晨:我是土生土长的武汉人,1985-1989年间在武汉大学求学,完成我的学士学位。本科毕业后来到美国,在阿拉巴马大学和霍华休斯医学院完成博士学位的学习,师从Max Cooper博士,他是美国科学院院士也是首个发现B细胞的科学家。博士毕业之后,我在耶鲁大学从事博士后训练,师从Richard Flavell博士,Richard Flavell也是美国科学院院士,英国皇家学会成员,他拥有世界上最成功的免疫学实验室之一。

 

生物通:您目前还从事免疫学方面的研究吗?可以介绍一下您的研究领域吗?

 

董晨:我主要是在分子和细胞层面研究免疫应答机制以及为何免疫失调引发多种疾病,比如说,免疫缺陷、自体免疫疾病以及过敏等方面的分子机制。我们这些研究也有助于理解和治疗感染性疾病和癌症。

 

在最近的几年,我主要集中研究T淋巴细胞,包括研究免疫激活和免疫耐受产生的调节机理以及研究一些新型的T细胞分化途径。到目前为止,我们已经发现了一些新的CD4+辅助性T细胞亚型,如Th17细胞。

 

最近我们发现一种辅助性T细胞,名为滤辅助性T细胞(T follicular helperTfh),为新的T细胞分化通路,并有其独特的转录分子,这篇文章发表在8月的Science上。


生物通:能介绍一下您新发现的这类滤泡辅助T细胞分化通路吗?

董晨:滤泡辅助T细胞(T follicular helperTfh)存在于小鼠和人类体内,它对体液免疫具有重要的调控作用,如果Tfh过度可能导致自体免疫疾病的的发生如类风湿性关节炎和狼疮。

 

然而,Tfh细胞的发育分化过程科学家们却一直不清楚,我们也不清楚Tfh与其他辅助性T细胞间的相互作用。去年,我们研究发现Tfh的发育其实不遵循Th1Th2或是Th17途径,但是却依赖于IL-6IL-6STAT3,这一新发现的成果我们当时发表在了Immunity上。

 

今年我们进一步研究发现,在Tfh细胞中Bcl6其实是选择性地表达,它控制Tfh细胞的多个基因的表达,并且还具有抑制Th1Th2Th17分化的功能。更重要的是,我们还发现Bcl6缺陷的T细胞不能发育为Tfh,这将导致小鼠无法对外来抗原产生正常的免疫应答,无法生成正常抗体。

 

这些研究数据不仅表明,Bcl6是调节Tfh细胞发育的重要转录因子,而且也验证了我们的猜测,Tfh是一类新型的辅助性T细胞分化通路。

 

生物通: 您是用什么方式或是模型研究Bcl6表达对T细胞的影响的?

董晨:我们用小鼠模型研究Bcl6的功能,将小鼠的bc6基因敲除掉,并通过逆转录病毒在小鼠的T细胞内过度表达Bcl6来研究Bcl6的功能。

 

生物通:这项研究成果对免疫学理论有什么影响?有哪些临床上的意义?

 

董晨:我们的研究不仅证实了Bcl6Tfh细胞的调节作用,还证实了Tfh是一类新的辅助性T细胞。Tfh是一类独特的辅助性T细胞,这丰富了免疫学理论,给免疫学增添了新的内容。

 

这些理论对了解自体免疫疾病的机制有重要的意义,可能对研发自体免疫疾病的新疗法具有重要的指导意义。

生物通:您在国外多年,能谈谈您对中国科学发展的看法吗?


董晨:这些年,我有机会接触到中国的免疫学家。在免疫学界而言,我认为中国免疫学会的理事长曹雪涛博士做得十分的出色,这些年中国在免疫学方面取得了快速的发展。我认同曹博士的理念,免疫学不仅仅是基础学科,免疫学更是一门应用性学科和系统生物学,很多免疫疾病是影响人类健康的重要疾病。我认为,中国应该把免疫学方面的基础研究作为一大重点,同时加强免疫学的临床研究,加速理论研究向临床应用方面的转化。我期待与中国的科学家在这方面有更多的合作互相促进。

 

后记

采访董晨教授很顺利,他十分的亲切。严谨的董教授一字一句的修改我的采访稿,最终呈现在读者面前的都是董教授亲自批改的稿件。我想,做学问的人的确应该有这份严谨的坚持。

(生物通  张欢)

 

Name

 Chen Dong, Ph.D.

 

Position Title

                       Professor

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training

INSTITUTION AND LOCATION

DEGREE

(if applicable)

YEAR(s)

FIELD OF STUDY

Wuhan University, Wuhan,China

University of Alabama, Birmingham, AL

Yale University, New Haven, CT

B.S.

Ph.D.

Postdoctoral fellowship

1989

1996

1997-2000

Cell Biology

Cell and Molecular Biology

Immunobiology

RESEARCH AND PROFESSIONAL EXPERIENCE:  Concluding with present position, list, in chronological order, previous employment, experience, and honors.  Include present membership on any Federal Government public advisory committee.  List, in chronological order, the title, all authors and completed references to all publications during the past three years and to representative earlier publications pertinent to this application.  If the list of publications in the last three years exceeds two pages, select the most pertinent publications.  DO NOT EXCEED TWO PAGES.

 

PROFESSIONAL EXPERIENCE:

1990-1996                                          Graduate Student, Department of Microbiology, University of Alabama at Birmingham,

                                    Mentor: Max D. Cooper, M.D.

1997-2000                     Postdoctoral Associate, Section of Immunobiology, Yale University School of Medicine

                                    New Haven, CT, Supervisor: Richard A. Flavell, Ph.D

2000-2004                     Assistant Professor, Department of Immunology, University of Washington School of Medicine, Seattle, WA

2004-2008                     Associate Professor (tenured), Department of Immunology, University of Texas MD Anderson Cancer Center

2008-                           Professor (tenured), Department of Immunology, University of Texas MD Anderson Cancer Center

2008-                           Director, Center for Inflammation and Cancer, MD Anderson Cancer Center

 

awards, Honors and Professional activities:

1999-2000                     Arthritis Foundation Postdoctoral Fellowship

2000 –2005                   Arthritis Investigator Award, Arthritis Foundation

2001                             Pfizer-Showell Travel Award, American Association of Immunologists

2002-2003                     Basil O’Connor Starter Investigator award, March of Dimes Foundation

2002                     Young Investigator Award (1st Prize), International Cytokine Society

2003                             FOCIS 2003 Travel Award, Federation of Clinical Immunology Societies

2003-2008                     Contributing Faculty Member, Faculty of 1000 Biology, Immunology Faculty, Leukocyte Activation Section

2003-2009            Cancer Research Institute Investigator Award

2004-present         MD Anderson Cancer Center Research Trust Fellow

2004                             Milstein Young Investigator award, International Society of Interferon and Cytokine Research

2005                             Organizer, Symposium “Gene Regulation and Function in Health and Diseases”, New Haven, CT.

2006-2011                                          Editorial Board member, Journal of Biological Chemistry

2007-2010                                          American Lung Association Career Investigator Award

2007-2010                     MD Anderson Cancer Center Faculty Scholar Award in Research

2008-2013                     Leukemia and Lymphoma Society Scholar Award

2009                             Primary organizer and speaker, Keystone Symposium “TH17 cells in Health and Diseases”, Vancouver, Canada

2009                            American Association of Immunologists BD Biosciences Investigator Award for outstanding, early-career research contributions to the field of immunology

 

SELECTED PUBLICATIONS (from total 100):

1.       Dong, C.*, Yang, D. D.*, Wysk, M., Whitmarsh, A. J., Davis, R. J., and Flavell, R. A. Defective T cell differentiation in the absence of Jnk1. (1998) Science. 282: 2092-2095 (* contribute equally).

2.       Dong, C., Yang, D. D., Tournier, C., Whitmarsh, A. J., Xu, J., Davis, R. J., and Flavell, R. A. JNK is required for effector T cell function but not for T cell activation. (2000) Nature. 405: 91-94.

3.       Dong, C., Juedes, A. E., Temann, U.-A., Shresta, S., Allison, J. P., Ruddle, N. H. and Flavell, R. A. ICOS Costimulatory Receptor Is Essential for T-cell Activation and Function. (2001) Nature. 409:97-101.

4.       Dong, C., Davis, R. J. and Flavell, R. A. MAP kinases in the immune response (Review). (2002) Annual Review of Immunology. 20:55-72.

5.       Sun, M., Richards, S., Prasad, D. V. R., Mai, X. M., Rudensky, A. and Dong, C. Characterization of mouse and human B7-H3 genes. (2002) Journal of Immunology. 168:6294.

6.       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.

7.       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.

8.       Dong, C. and Nurieva, R. Regulation of immune and autoimmune responses by ICOS. (Review). (2003) Journal of Autoimmunity. 21:255-260.

9.       Nurieva, R., Mai, X. M., Forbush, K., Ho, I.-C., 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.

10.   Prasad, D. V. R., Nguyen, T., Li, Z., Yang, Y., Duong, J., Wang, Y., and Dong, C. Murine B7-H3 is a negative regulator of T cells. (2004) Journal of Immunology. 173:2500-2506.

11.   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.

12.   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.

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

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

15.     Nguyen, T., Liu, X., Zhang, Y., and Dong, C. BTNL2, a butyrophilin-like molecule that functions to inhibit T cell activation. (2006) Journal of Immunology. 176:7354–7360

16.   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.

17.   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.

18.     Martin-Orozco, N., Wang, Y.-H., Yagita, H. and Dong, C. Cutting Edge: PD-1-PD-L1 interaction is required for CD8+ T cell tolerance to tissue antigens. (2006) Journal of Immunology. 177: 8291–8295.

19.   Chang, S. H., Park, H., and Dong, C. Act1 is an immediate and essential signaling component of IL-17 receptor. (2006) Journal of Biological Chemistry. 281: 35603-35607.

20.   Akimzhanov, A., Yang, X. O. and Dong, C. Chromatin Remodeling at IL-17-IL-17F cytokine gene locus during inflammatory helper T cell differentiation. (2007) Journal of Biological Chemistry 282:5969-5972.

21.   Yang, Y., Liu, X., Nguyen, T., Bishop, C., Graf, D. and Dong, C. Characterization of B7S3 as a novel negative regulator of T cells. (2007) Journal of Immunology. 178: 3661–3667.

22.   Yang, X. O., Panopoulos, A. D., Nurieva, R., Chang, S. H., Wang, D., Watowich, S. S., and Dong, C. Stat3 regulates cytokine-mediated generation of inflammatory helper T cells. (2007) Journal of Biological Chemistry 282: 9358-9363.

23.   Nurieva, R.I, Chuvpilo, S., Wieder, E. D., Elkon, K. B., Locksley, R., Serfling, E. and Dong, C. A costimulation-initiated signaling pathway regulates NFATc1 transcription in T lymphocytes. (2007) Journal of Immunology. 179: 1096–1103.

24.   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 pro-allergic type 2 responses. (2007) Journal of Experimental Medicine. 204:1509-1517.

25.   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. (2007) Nature. 448: 480-483.

26.   Martin-Orozco, N. and Dong, C. Inhibitory “co-stimulatory” molecules and anti-tumor immunity (Review). Seminars in Cancer Biology. (2007) Seminars in Cancer Biology. 17: 288–298.

27.   Chung, Y. S., Qin, H., Kang, C.-Y., Kim, S., Kwak, L. W., and Dong, C. An NKT cell-mediated autologous vaccine generates potent CD4+ T-cell-dependent anti-lymphoma immunity. (2007) Blood. 110:2013-2019.

28.   Pappu, B. and Dong, C. Unit 6.25 Measurement of interleukin 17. (2007) In: Current Protocols in Immunology. Coligan, J. E., Kruisbeek, A. M., Margulies, D. H., Shevach, E. M., Strober, W. Unlimited Learning Resources, LLC., 6.25.1-6.25.8.

29.   Yang, X. O., Pappu, B., Nurieva, R., Akimzhanov, A., Kang, H. S., Chung, Y., Ma, L., Panopoulos, A. D., Schluns, K., Watowich, S. S., Tian, Q., Jetten, A. M. and Dong, C. TH17 lineage differentiation programmed by orphan nuclear receptors RORa and RORg. (2008) Immunity. 28, 29–39.

30.   Chung, Y. S., Nurieva, R., Esashi, E., Wang, Y.-H., Zhou, D., Gapin, L., and Dong, C. A Critical Role of Costimulation During Intrathymic Development of Invariant NKT cells. (2008) Journal of Immunology. 180:2276-2783.

31.   Pappu, B. P., Angkasekwinai, P. and Dong, C. Regulatory mechanisms of helper T cell differentiation-New lessons learnt from interleukin 17 family cytokines (Review). (2008) Pharmacology & Therapeutics. 117:374–384.

32.   Dong, C. TH17 cells in development: an updated view of their molecular identity and genetic programming (Review). (2008) Nature Review Immunology. 8:337-348.

33.   Pappu, B. P., Borodovsky, A., Zheng, T., Yang, X., Wu, P., Dong, X., Weng, S., Browning, B., Scott, M., Ma, L., Tian, Q., Schneider, P., Flavell, R. A., Dong, C. * and Burkly, L. C. * TL1A-DR3 interaction regulates Th17 cell proliferation and Th17-mediated autoimmune disease.(2008) Journal of Experimental Medicine. 205:1049-1062. (* co-correspondent authors)

34.   Yang, X. O., Chang, S. H., Park, H., Nurieva, R., Wang, Y.-H., Zhu, Z. and Dong, C. Regulation of inflammatory responses by IL-17F. (2008) Journal of Experimental Medicine 205:1063-1075.

35.   Yang, X. O., Nurieva, R., Martinez, G. J., Chung, Y., Kang, H. S., Pappu, B. P., Shah, B., Chang, S. H., Schluns, K. S., Watowich, S. S., Feng, X., Jetten, A. M. and Dong, C. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. (2008) Immunity. 29:44-56.

36.   Nurieva, R. I., Chung, Y., Hwang, D., Yang, X. O., Kang, H. S., Ma, L., Wang, Y.-H., Watowich, S. S., Jetten, A. M., Tian, Q. and Dong, C. Generation of follicular helper T cells is mediated by IL-21 but independent of TH1, TH2 or TH17 lineages. (2008) Immunity. 29:138-149.

37.   Dong, C. Regulation and pro-inflammatory function of interleukin 17 family cytokines. (Review) (2008) Immunological Reviews. 226:80-86.

38.   Martinez, G. J., Nurieva, R. I., Yang, X. O. and Dong, C. Regulation and function of pro-inflammatory TH17 cells. In: The Year in Immunology 2008. Rose, N. (2008) Annals of New York Academy of Sciences. 188-211.

39.   Yamazaki, T., Yang, X. O., Chung, Y., Fukunaga, A., Nurieva, R., Pappu, B., Martin-Orozco, N., Kang, H. S., Ma, L., Panopoulos, A. D., Craig, S., Watowich, S. S., Jetten, A. M., Tian, Q., and Dong, C. CCR6 regulates the migration of inflammatory and regulatory T cells. (2008) Journal of Immunology. 181:8391-8401.

40.   Nurieva, R. I. and Dong, C. Keeping Autoimmunity in Check: How to Control a Th17 Cell Controller. (Preview). (2008) Immunity. 29:841-843.

41.   Angkasekwinai, P. and Dong, C. IL-25, another promoter of allergy. (2009) In: Role or TH17 in inflammation and autoimmune disease. Ryffel, B. & di Padova, F. 69-83.

42.   Martin-Orozco, N., Chang, S. H., Chung, Y., Wang, Y.- H. and Dong, C. Th17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into Th1 cells. (2009) European Journal of Immunology 39: 216–224.

43.   Chung, Y. and Dong, C. Don’t leave home without it: the IL-23 visa to TH-17 cells. (News and Views) (2009) Nature Immunology. 10:236-238.

44.   Nurieva, R., Yang, X. O., Chung, Y. and Dong, C. Cutting Edge: In vitro generated TH17 cells maintain their cytokine expression program in normal but not lymphopenic hosts. (2009) Journal of Immunology. 182: 2565–2568.

45.   Dong, C. Mouse Th17 cells: current understanding on their generation and regulation. (Review). (2009) European Journal of Immunology. 39: 634–675.

46.   Chang, S. H. and Dong, C. IL-17F: regulation, signaling and function in inflammation (Review). (2009) Cytokine. 46:7-11.

47.   Liu , X., Alexiou, M., Martin-Orozco , N., Chung , Y., Nurieva , R., Ma , L., Tian, Q., Kollias, G., Lu, S., Graf, D. and Dong, C. Cutting Edge: A critical role of BTLA in peripheral T cell tolerance induction. (2009) Journal of Immunology. 182: 4516–4520.

48.   Chung, Y., Chang, S. H., Martinez, G. J., Yang, X. O., Nurieva, R., Kang, H. S., Ma, L., Watowich, S. S., Jetten, A., Tian, Q. and Dong, C. Critical regulation of early Th17 cell differentiation by IL-1 signaling. (2009) Immunity. 30, 576–587.

49.   Nurieva, R., Liu, X. and Dong, C. Yin-Yang of costimulation: crucial controls of immune tolerance and function. (Review). (2009) Immunological Reviews. 229: 88–100.

50.   Martin-Orozco, N. and Dong, C. IL-23/IL-17 axis of inflammation in cancer, a friend or foe? (Review) (2009) Current Opinion in Investigational Drugs. 10:543-549.

51.   Nurieva, R. I., Chung, Y., Martinez, G. J., Yang, X. O., Tanaka, S., Matskevitch, T. D., Wang, Y.-H. and Dong, C. Bcl6 mediates the development of T follicular helper cells. Science. In press.

 

SELECTED ONGOING Research Support.

1 U19 AI071130-01- Liu, YJ (PI)                                                           7/1/2006-6/30/2011          

Title: Texas Medical Center Asthma and Allergic Diseases Cooperative Research Center

National Institute of Health

Project 4. Regulation of TSLP by inflammatory TH cells- Dong, C. (Leader)                               

 

R01 AI054912-01-Dong, C. (P.I.)                                  1/1/07-12/31/11    

National Institute of Health                                           

Title: Immune Tolerance Mediated by negative Costimulatory Molecules

 

RO1 AR050772- Dong, C. (P.I.)                                                            9/1/03-8/31/12   

National Institute of Health                                                  

Title: Transcriptional regulation of inflammatory T cell differentiation.

 

SCOR grant- Kwak, L (PI)                                                                    10/1/2007-9/30/12     

Project 1- Dong, C. (Leader)                                                                                                    

Leukemia and Lymphoma Society                          

Title: Modulating the innate-adaptive immunity interface to boost lymphoid tumor vaccine responses

 

RO1 AI50761- Dong, C. (P.I.)                                                              12/01/2001 – 04/30/2011       

NIH                                                

Title: Signal Transduction and Cytokine Gene Regulation by Grail

 

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