title: MicroRNAs targeting TGFβ signalling underlie the regulatory T cell defect in multiple sclerosis.
abstract: Transforming growth factor beta (TGFβ) signalling is critical for regulatory T cell development and function, and regulatory T cell dysregulation is a common observation in autoimmune diseases, including multiple sclerosis. In a comprehensive miRNA profiling study of patients with multiple sclerosis naïve CD4 T cells, 19 differentially expressed miRNAs predicted to target the TGFβ signalling pathway were identified, leading to the hypothesis that miRNAs may be responsible for the regulatory T cell defect observed in patients with multiple sclerosis. Patients with multiple sclerosis had reduced levels of TGFβ signalling components in their naïve CD4 T cells. The differentially expressed miRNAs negatively regulated the TGFβ pathway, resulting in a reduced capacity of naïve CD4 T cells to differentiate into regulatory T cells. Interestingly, the limited number of regulatory T cells, that did develop when these TGFβ-targeting miRNAs were overexpressed, were capable of suppressing effector T cells. As it has previously been demonstrated that compromising TGFβ signalling results in a reduced regulatory T cell repertoire insufficient to control autoimmunity, and patients with multiple sclerosis have a reduced regulatory T cell repertoire, these data indicate that the elevated expression of multiple TGFβ-targeting miRNAs in naïve CD4 T cells of patients with multiple sclerosis impairs TGFβ signalling, and dampens regulatory T cell development, thereby enhancing susceptibility to developing multiple sclerosis.
authors.affiliation: Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, OH, USA Biomedical Sciences Graduate Program, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Severin
authors.affiliation: Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, OH, USA Molecular, Cellular and Developmental Biology Program, The Ohio State University, Columbus, OH, USA.
authors.forename: Priscilla W
authors.initials: PW
authors.lastname: Lee
authors.affiliation: Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Selhorst
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Gormley
authors.affiliation: Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Pei
authors.affiliation: Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Health and Rehabilitation Sciences, The Ohio State University Wexner Medical Center, Columbus, OH, USA Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Mireia
authors.initials: M
authors.lastname: Guerau-de-Arellano
authors.affiliation: Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Racke
authors.affiliation: Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, OH, USA Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH, USA amy.lovett-racke@osumc.edu.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Lovett-Racke
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002454:Cell Differentiation; D015870:Gene Expression; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009103:Multiple Sclerosis / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D016212:Transforming Growth Factor beta
keywords: TGFbeta; Tregs; microRNA; multiple sclerosis