徐墨 博士 研究員

Mo Xu, Ph.D.

Assistant Investigator, NIBS, Beijing

Phone:86-10-80726688

Fax:86-10-80726689

Email:xumo@nibs.ac.cn

教育經(jīng)歷 Education

2011    北京生命科學(xué)研究所（朱冰實(shí)驗(yàn)室） 博士

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

2006    北京師范大學(xué) 生命科學(xué)學(xué)院 學(xué)士

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

工作經(jīng)歷 Professional Experience

研究概述

我們實(shí)驗(yàn)室的研究興趣集中在兩個(gè)方面：（1）T細(xì)胞免疫；（2）II型免疫應(yīng)答的先天識(shí)別機(jī)制。

（1）T細(xì)胞免疫

我們主要關(guān)注腸黏膜組織中的和與慢性炎癥相關(guān)的T細(xì)胞應(yīng)答。

黏膜組織是包括細(xì)菌、真菌、病毒、寄生蟲在內(nèi)的多種病原體入侵的主要途徑和寄生場(chǎng)所。該組織富集了大量功能各異的免疫細(xì)胞，時(shí)刻防備各類病原侵襲。與此同時(shí)，動(dòng)物的消化道，尤其是大腸，是為數(shù)眾多的共生微生物的定居場(chǎng)所。這些腸道共生微生物輔助宿主從食物中吸收營(yíng)養(yǎng)物質(zhì)，促進(jìn)宿主免疫系統(tǒng)的成熟并維持其正常功能，它們的代謝產(chǎn)物進(jìn)入宿主體內(nèi)，影響多種生物學(xué)過(guò)程。因此，黏膜免疫系統(tǒng)在警惕病原體侵犯的同時(shí)，又要對(duì)共生微生物保持耐受。對(duì)黏膜共生菌群的過(guò)度反應(yīng)，會(huì)導(dǎo)致以炎性腸病（inflammatory bowel disease, IBD）為代表的自身免疫疾病。我們將結(jié)合免疫遺傳學(xué)、細(xì)胞生物學(xué)、基因組學(xué)等方法，研究不同免疫細(xì)胞特別是幾種T細(xì)胞亞群在黏膜免疫中扮演的角色。

慢性炎癥一直是人類健康的重要威脅， 嚴(yán)重影響患者的生活質(zhì)量。包括炎癥性腸病、類風(fēng)濕性關(guān)節(jié)炎、多發(fā)性硬化在內(nèi)的各種自身免疫性疾病，都屬于慢性炎癥范疇。統(tǒng)計(jì)表明，占總?cè)丝诒壤?%-5%的人群，會(huì)在一生中受到某種自身免疫性疾病的困擾，且近半個(gè)世紀(jì)來(lái)發(fā)病率在世界范圍內(nèi)逐年上升。此外，近幾年的研究表明，神經(jīng)系統(tǒng)的慢性炎癥參與帕金森綜合癥、阿爾茨海默癥等神經(jīng)退行性疾病的發(fā)病。在免疫系統(tǒng)中，不同亞群的輔助T細(xì)胞（包括炎性Th1、Th17等）對(duì)慢性炎癥的發(fā)病起到關(guān)鍵貢獻(xiàn)，而調(diào)節(jié)性T細(xì)胞（regulatory T cells，Treg cells）抑制炎癥反應(yīng)，對(duì)維持組織穩(wěn)態(tài)不可或缺。我們將研究各種T細(xì)胞亞群在慢性炎癥中發(fā)揮的作用，以及它們受免疫系統(tǒng)其它組分調(diào)控的機(jī)制。

我們實(shí)驗(yàn)室所擅長(zhǎng)的T細(xì)胞受體克隆分析、抗原表位鑒定等技術(shù)將在上述研究中發(fā)揮重要作用。

（2）II型免疫應(yīng)答的先天識(shí)別機(jī)制。

根據(jù)應(yīng)答效應(yīng)和參與應(yīng)答的淋巴細(xì)胞亞群的不同，免疫反應(yīng)可被劃分為三型：（1）負(fù)責(zé)對(duì)抗細(xì)胞內(nèi)寄生的病原體（如病毒、結(jié)核桿菌）的I型免疫反應(yīng)，參與應(yīng)答的主要包括Th1細(xì)胞、CD8 T細(xì)胞、一型先天淋巴細(xì)胞（Type I Innate lymphoid cells, ILC1s）和自然殺傷（Natural Killer, NK）細(xì)胞；（2）負(fù)責(zé)對(duì)抗寄生蟲侵染，并可導(dǎo)致過(guò)敏的II型免疫反應(yīng)，參與應(yīng)答的主要有Th2細(xì)胞、二型先天淋巴細(xì)胞（Type II Innate lymphoid cells, ILC2s）、和分泌IgE抗體的B細(xì)胞；（3）負(fù)責(zé)對(duì)抗胞外寄生的細(xì)菌和真菌的III型反應(yīng)，參與者主要包括Th17細(xì)胞、三型先天淋巴細(xì)胞（Type III Innate lymphoid cells, ILC3s）等。在缺少佐劑（adjuvant）輔助的情況下，單純使用經(jīng)過(guò)純化的抗原蛋白，無(wú)法有效地誘導(dǎo)任一類型的免疫應(yīng)答。據(jù)此，Charles Janeway Jr. 在1989年預(yù)見(jiàn)性地推斷了先天免疫受體假說(shuō)——先天免疫系統(tǒng)識(shí)別微生物的特征，進(jìn)而有針對(duì)性地指導(dǎo)不同類型的效應(yīng)應(yīng)答。Jules Hoffmann于1996年在果蠅中發(fā)現(xiàn)了第一個(gè)先天免疫受體——Toll樣受體（Toll-like receptor, TLR），Bruce Beutler于1998年報(bào)道了第一個(gè)哺乳動(dòng)物先天免疫受體TLR-4，以實(shí)驗(yàn)證實(shí)了Janeway的假說(shuō)。此后，識(shí)別各類病原相關(guān)分子模式（Pathogen-associated molecular patterns, PAMPs）的多個(gè)家族的先天免疫受體相繼被發(fā)現(xiàn)，它們的識(shí)別機(jī)制逐步被解析。同時(shí)， 先天免疫受體在識(shí)別各種病原特征之后，如何特異指導(dǎo)下游不同類型的效應(yīng)應(yīng)答，也獲得了一定程度的闡釋。遺憾的是，目前已知的先天免疫識(shí)別機(jī)制，均是指導(dǎo)I型和III型免疫反應(yīng)，而我們對(duì)指導(dǎo)II型免疫反應(yīng)的先天識(shí)別原理幾乎完全沒(méi)有了解。因此，我們實(shí)驗(yàn)室計(jì)劃通過(guò)遺傳學(xué)的方法尋找誘導(dǎo)II型免疫應(yīng)答的先天免疫識(shí)別機(jī)制，并運(yùn)用動(dòng)物模型研究相關(guān)分子在各種生理、病理過(guò)程中的功能。這個(gè)方向的研究有可能為開(kāi)發(fā)針對(duì)II型免疫反應(yīng)導(dǎo)致的疾病（如過(guò)敏性哮喘等）的新療法提供理論依據(jù)。

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)