title: Systems biologic analysis of T regulatory cells genetic pathways in murine primary biliary cirrhosis.
abstract: CD4(+)Foxp3(+) regulatory T cells (Tregs) play a non-redundant role in control of excessive immune responses, and defects in Tregs have been shown both in patients and murine models of primary biliary cirrhosis (PBC), a progressive autoimmune biliary disease. Herein, we took advantage of a murine model of PBC, the dominant negative transforming growth factor β receptor II (dnTGFβRII) mice, to assess Treg genetic defects and their functional effects in PBC. By using high-resolution microarrays with verification by PCR and protein expression, we found profound and wide-ranging differences between dnTGFβRII and normal, wild type Tregs. Critical transcription factors were down-regulated including Eos, Ahr, Klf2, Foxp1 in dnTGFβRII Tregs. Functionally, dnTGFβRII Tregs expressed an activated, pro-inflammatory phenotype with upregulation of Ccl5, Granzyme B and IFN-γ. Genetic pathway analysis suggested that the primary effect of loss of TGFβ pathway signaling was to down regulate immune regulatory processes, with a secondary upregulation of inflammatory processes. These findings provide new insights into T regulatory genetic defects; aberrations of the identified genes or genetic pathways should be investigated in human PBC Tregs. This approach which takes advantage of biologic pathway analysis illustrates the ability to identify genes/pathways that are affected both independently and dependent on abnormalities in TGFβ signaling. Such approaches will become increasingly useful in human autoimmunity.
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China. Electronic address: wangyh8@mail.ustc.edu.cn.
authors.forename: Yin-Hu
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China. Electronic address: ywei0702@mail.ustc.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China. Electronic address: yjingb@mail.ustc.edu.cn.
authors.forename: Jing-Bo
authors.initials: JB
authors.lastname: Yang
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China. Electronic address: jyanjie@mail.ustc.edu.cn.
authors.forename: Yan-Jie
authors.initials: YJ
authors.lastname: Jia
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China. Electronic address: wayne012@mail.ustc.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA. Electronic address: megershwin@ucdavis.edu.
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.affiliation: Division of Immunology, Allergy and Rheumatology, University of Cincinnati, Cincinnati, OH 45220, USA. Electronic address: wridg1@gmail.com.
authors.forename: William M
authors.initials: WM
authors.lastname: Ridgway
authors.affiliation: Liver Immunology Laboratory, Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China; Innovation Center for Cell Biology, Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China. Electronic address: zxlian1@ustc.edu.cn.
authors.forename: Zhe-Xiong
authors.initials: ZX
authors.lastname: Lian
mesh_terms: D000818:Animals; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D008105:Liver Cirrhosis, Biliary / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D046228:Microarray Analysis; D009154:Mutation / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D018946:Chemokine CCL5; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018836:Inflammation Mediators; D018125:Receptors, Transforming Growth Factor beta; D014157:Transcription Factors; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D053804:Granzymes
keywords: Cholangitis; Primary biliary cirrhosis; Regulatory T cells; Transcription profile and pathway analysis