title: A miR-155-Peli1-c-Rel pathway controls the generation and function of T follicular helper cells.
abstract: MicroRNA (miRNA) deficiency impairs the generation of T follicular helper (Tfh) cells, but the contribution of individual miRNAs to this phenotype remains poorly understood. In this study, we performed deep sequencing analysis of miRNAs expressed in Tfh cells and identified a five-miRNA signature. Analyses of mutant mice deficient of these miRNAs revealed that miR-22 and miR-183/96/182 are dispensable, but miR-155 is essential for the generation and function of Tfh cells. miR-155 deficiency led to decreased proliferation specifically at the late stage of Tfh cell differentiation and reduced CD40 ligand (CD40L) expression on antigen-specific CD4(+) T cells. Mechanistically, miR-155 repressed the expression of Peli1, a ubiquitin ligase that promotes the degradation of the NF-κB family transcription factor c-Rel, which controls cellular proliferation and CD40L expression. Therefore, our study identifies a novel miR-155-Peli1-c-Rel pathway that specifically regulates Tfh cell generation and function.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361005, China cxiao@scripps.edu whliu@xmu.edu.cn guofu@xmu.edu.cn.
authors.forename: Wen-Hsien
authors.identifier: 0000-0003-2500-3892
authors.initials: WH
authors.lastname: Liu
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037 Division of Biomedical Convergence/Institute of Bioscience and Biotechnology, College of Biomedical Science, Kangwon National University, Chuncheon 24341, Republic of Korea.
authors.forename: Seung Goo
authors.initials: SG
authors.lastname: Kang
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Division of Biological Sciences, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Cheng-Jang
authors.initials: CJ
authors.lastname: Wu
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Hyun Yong
authors.initials: HY
authors.lastname: Jin
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Maine
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Yi
authors.identifier: 0000-0003-1372-2101
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Jovan
authors.initials: J
authors.lastname: Shepherd
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Mohsen
authors.identifier: 0000-0001-7770-5314
authors.initials: M
authors.lastname: Sabouri-Ghomi
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Alicia
authors.initials: A
authors.lastname: Gonzalez-Martin
authors.affiliation: Department of Ophthalmology/Kresge Eye Institute, School of Medicine, Wayne State University, Detroit, MI 48202 Department of Anatomy and Cell Biology, School of Medicine, Wayne State University, Detroit, MI 48202.
authors.forename: Shunbin
authors.identifier: 0000-0002-6140-0943
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA 90095.
authors.forename: Alexander
authors.identifier: 0000-0002-5607-3845
authors.initials: A
authors.lastname: Hoffmann
authors.affiliation: Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037.
authors.forename: Ye
authors.identifier: 0000-0001-5012-4309
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Division of Biological Sciences, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Li-Fan
authors.identifier: 0000-0002-9727-0036
authors.initials: LF
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361005, China.
authors.forename: Nengming
authors.identifier: 0000-0001-5417-707X
authors.initials: N
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361005, China cxiao@scripps.edu whliu@xmu.edu.cn guofu@xmu.edu.cn.
authors.forename: Guo
authors.initials: G
authors.lastname: Fu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361005, China Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037 cxiao@scripps.edu whliu@xmu.edu.cn guofu@xmu.edu.cn.
authors.forename: Changchun
authors.identifier: 0000-0001-8754-3208
authors.initials: C
authors.lastname: Xiao
mesh_terms: D000818:Animals; D023201:CD40 Ligand / Q000032:analysis; D002454:Cell Differentiation; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology; D009687:Nuclear Proteins / Q000502:physiology*; D020569:Proto-Oncogene Proteins c-rel / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; C543802:Mirn183 microRNA, mouse; C541554:Mirn96 microRNA, mouse; D016328:NF-kappa B; D009687:Nuclear Proteins; D020569:Proto-Oncogene Proteins c-rel; D023201:CD40 Ligand; D044767:Ubiquitin-Protein Ligases; C418046:Peli1 protein, mouse