徐墨 博士 研究员

Mo Xu, Ph.D.

Assistant Investigator, NIBS, Beijing

Phone:86-10-80726688

Fax:86-10-80726689

Email:xumo@nibs.ac.cn

教育经历 Education

2011    北京生命科学研究所（朱冰实验室） 博士

Ph.D. in Biochemistry and Molecular Biology, National Institute of Biological Science (NIBS), Beijing, China. (Lab of Dr. Bing Zhu)

2006    北京师范大学 生命科学学院 学士

B.S., College of Life Science, Beijing Normal University, Beijing, China

工作经历 Professional Experience

研究概述

我们实验室的研究兴趣集中在两个方面：（1）T细胞免疫；（2）II型免疫应答的先天识别机制。

（1）T细胞免疫

我们主要关注肠黏膜组织中的和与慢性炎症相关的T细胞应答。

黏膜组织是包括细菌、真菌、病毒、寄生虫在内的多种病原体入侵的主要途径和寄生场所。该组织富集了大量功能各异的免疫细胞，时刻防备各类病原侵袭。与此同时，动物的消化道，尤其是大肠，是为数众多的共生微生物的定居场所。这些肠道共生微生物辅助宿主从食物中吸收营养物质，促进宿主免疫系统的成熟并维持其正常功能，它们的代谢产物进入宿主体内，影响多种生物学过程。因此，黏膜免疫系统在警惕病原体侵犯的同时，又要对共生微生物保持耐受。对黏膜共生菌群的过度反应，会导致以炎性肠病（inflammatory bowel disease, IBD）为代表的自身免疫疾病。我们将结合免疫遗传学、细胞生物学、基因组学等方法，研究不同免疫细胞特别是几种T细胞亚群在黏膜免疫中扮演的角色。

慢性炎症一直是人类健康的重要威胁， 严重影响患者的生活质量。包括炎症性肠病、类风湿性关节炎、多发性硬化在内的各种自身免疫性疾病，都属于慢性炎症范畴。统计表明，占总人口比例4%-5%的人群，会在一生中受到某种自身免疫性疾病的困扰，且近半个世纪来发病率在世界范围内逐年上升。此外，近几年的研究表明，神经系统的慢性炎症参与帕金森综合症、阿尔茨海默症等神经退行性疾病的发病。在免疫系统中，不同亚群的辅助T细胞（包括炎性Th1、Th17等）对慢性炎症的发病起到关键贡献，而调节性T细胞（regulatory T cells，Treg cells）抑制炎症反应，对维持组织稳态不可或缺。我们将研究各种T细胞亚群在慢性炎症中发挥的作用，以及它们受免疫系统其它组分调控的机制。

我们实验室所擅长的T细胞受体克隆分析、抗原表位鉴定等技术将在上述研究中发挥重要作用。

（2）II型免疫应答的先天识别机制。

根据应答效应和参与应答的淋巴细胞亚群的不同，免疫反应可被划分为三型：（1）负责对抗细胞内寄生的病原体（如病毒、结核杆菌）的I型免疫反应，参与应答的主要包括Th1细胞、CD8 T细胞、一型先天淋巴细胞（Type I Innate lymphoid cells, ILC1s）和自然杀伤（Natural Killer, NK）细胞；（2）负责对抗寄生虫侵染，并可导致过敏的II型免疫反应，参与应答的主要有Th2细胞、二型先天淋巴细胞（Type II Innate lymphoid cells, ILC2s）、和分泌IgE抗体的B细胞；（3）负责对抗胞外寄生的细菌和真菌的III型反应，参与者主要包括Th17细胞、三型先天淋巴细胞（Type III Innate lymphoid cells, ILC3s）等。在缺少佐剂（adjuvant）辅助的情况下，单纯使用经过纯化的抗原蛋白，无法有效地诱导任一类型的免疫应答。据此，Charles Janeway Jr. 在1989年预见性地推断了先天免疫受体假说——先天免疫系统识别微生物的特征，进而有针对性地指导不同类型的效应应答。Jules Hoffmann于1996年在果蝇中发现了第一个先天免疫受体——Toll样受体（Toll-like receptor, TLR），Bruce Beutler于1998年报道了第一个哺乳动物先天免疫受体TLR-4，以实验证实了Janeway的假说。此后，识别各类病原相关分子模式（Pathogen-associated molecular patterns, PAMPs）的多个家族的先天免疫受体相继被发现，它们的识别机制逐步被解析。同时， 先天免疫受体在识别各种病原特征之后，如何特异指导下游不同类型的效应应答，也获得了一定程度的阐释。遗憾的是，目前已知的先天免疫识别机制，均是指导I型和III型免疫反应，而我们对指导II型免疫反应的先天识别原理几乎完全没有了解。因此，我们实验室计划通过遗传学的方法寻找诱导II型免疫应答的先天免疫识别机制，并运用动物模型研究相关分子在各种生理、病理过程中的功能。这个方向的研究有可能为开发针对II型免疫反应导致的疾病（如过敏性哮喘等）的新疗法提供理论依据。

Research Description

Our research will focus on two directions: (1) T cells responses in mucosal surface and chronic inflammation; and (2) Identification of Type II innate sensing mechanisms.

The mucosal surface of Gastrointestinal (GI) tract is one of the major sites of immunological challenge to host immune system. The host must be able to mount protective immune responses against invading pathogenic micro-organisms while, at the same time specifically not activating these mechanisms in response to dietary antigens or the beneficial commensal flora. At steady states, gut Th17 cells are co-exist in a well regulated balance with Foxp3+ Treg cells. Mechanisms underlying this homeostasis still remain elusive.

Chronic inflammation plays a central role in some of the most challenging diseases, including rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, type I diabetes, asthma, and even neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s. The strong association between specific alleles encoded within the MHC class II region and the development of autoimmune diseases indicate that CD4+ T cells are involved in the pathogenesis. The immune system needs to reach equilibrium that permits protective responses against pathogens while limits potential harmful responses targeting the “self” and provoking autoimmunity. How this balance is achieved through the interactions of different classes of T cells that have pro- or anti-inflammatory activity remains to be further explored.

We are employing Immune repertoire profiling and TCR transgenic strategies to study the role of distinct T cell subsets in the maintenance of gut homeostasis and the pathogenesis of chronic inflammation.

The immune system has tailored its effector functions to precisely respond to distinct microorganism species. Based on the different effector functions and involvement of T-helper cell and innate lymphoid cell (ILC) subsets, the innate and adaptive immune systems converge into three major kinds of effector immunity, which are usually categorized as type I, type II, and type II. During the past twenty years, the field of immunology has witnessed tremendous breakthroughs in how effector immune responses are instructed by the innate immune system. Several classes of pattern-recognition receptors (PRRs) have been identified and characterized in detail. However, the physiological roles of these PRRs are limited to the sensing of bacterial, virus and fungus colonization and instruction of type I and type III effector responses. How the innate sensing system recognizes worm infection and allergy, and consequently induces type II response remains largely unknown. Our lab will work on the sentinels of type II immune stimuli and characterize mechanisms of their recognition. The potential discoveries of this research will open up new avenues for understanding how innate immune recognitions induce distinct types of effector responses, and provide knowledge for developing novel therapies of allergic diseases such as asthma.

代表文章  Representative Publications

1. Xu M*, Pokrovskii M*, Ding Y, Yi R, Au C, Harrison OJ, Galan C, Belkaid Y, Bonneau R, Littman DR. c-Maf-dependent regulatory T cells mediate immunological tolerance to intestinal microbiota. Nature. 2018 Feb 15; 554(7692):373-377. PMCID: PMC5814346 (*Equal contribution, highlighted by Nature Review of Immunology)

2. Yang Y, Torchinsky MB, Gobert M, Xiong H, Xu M, Linehan JL, Alonzo F, Ng C, Chen A, Lin X, Sczesnak A, Liao JJ, Torres VJ, Jenkins MK, Lafaille JJ, Littman DR. Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature. 2014 Jun 5;510(7503):152-6.

3. Huang C, Zhang Z, Xu M, Li Y, Li Z, Ma Y, Cai T, Zhu B. H3.3-H4 tetramer splitting events feature cell-type specific enhancers. PLoS Genet. 2013 Jun;9(6):e1003558.

4. Yuan W, Wu T, Fu H, Dai C, Wu H, Liu N, Li X, Xu M, Zhang Z, Niu T, Han Z, Chai J, Zhou XJ, Gao S, Zhu B. Dense chromatin activates Polycomb repressive complex 2 to regulate H3 lysine 27 methylation. Science. 2012 Aug 24;337(6097):971-5.

5. Xu M, Wang W, Chen S#, Zhu B#. A model for mitotic inheritance of histone lysine methylation. EMBO Rep. 2011 Dec 23; 13(1):60-7. (#Co-correspondence)

6. Jing B, Xu S, Xu M, Li Y, Li S, Ding J, Zhang Y. Brush and spray: a high-throughput systemic acquired resistance assay suitable for large-scale genetic screening. Plant Physiol. 2011 Nov; 157(3):973-80.

7. Yuan W*, Xu M*, Huang C, Liu N, Chen S, Zhu B. H3K36 methylation antagonizes PRC2-mediated H3K27 methylation. J Biol Chem. 2011 Mar 11; 286 (10): 7983-9. (*Equal contribution)

8. Chen X, Xiong J, Xu M, Chen S, Zhu B. Symmetrical modification within a nucleosome is not required globally for histone lysine methylation. EMBO Rep. 2011 Mar; 12(3): 244-51.

9. Xu M*, Long C*, Chen X, Huang C, Chen S#, Zhu B#. Partitioning of histone H3-H4 tetramers during DNA replication-dependent chromatin assembly. Science. 2010 Apr 2; 328(5974): 94-8. (*Equal contribution; #Co-correspondence)

10. Jia G, Wang W, Li H, Mao Z, Cai G, Sun J, Wu H, Xu M, Yang P, Yuan W, Chen S, Zhu B. A systematic evaluation of the compatibility of histones containing methyl-lysine analogues with biochemical reactions. Cell Res. 2009 Oct; 19(10):1217-20.

Review

1. Huang C, Xu M, Zhu B. Epigenetic inheritance mediated by histone lysine methylation: maintaining transcriptional states without the precise restoration of marks? Philos Trans R Soc Lond B Biol Sci. 2013 Jan 5;368(1609):20110332.

2. Xu M, Zhu B. Nucleosome assembly and epigenetic inheritance. Protein Cell. 2010 Sep; 1(9):820-9.

Book Chapter

1. Xu M, Chen S#, Zhu B#. Investigating the cell cycle-associated dynamics of histone modifications using quantitative mass spectrometry. Methods Enzymol. 2012;512:29-55. (#Co-correspondence)