title: T Follicular Helper Cell-Dependent Clearance of a Persistent Virus Infection Requires T Cell Expression of the Histone Demethylase UTX.
abstract: Epigenetic changes, including histone methylation, control T cell differentiation and memory formation, though the enzymes that mediate these processes are not clear. We show that UTX, a histone H3 lysine 27 (H3K27) demethylase, supports T follicular helper (Tfh) cell responses that are essential for B cell antibody generation and the resolution of chronic viral infections. Mice with a T cell-specific UTX deletion had fewer Tfh cells, reduced germinal center responses, lacked virus-specific immunoglobulin G (IgG), and were unable to resolve chronic lymphocytic choriomeningitis virus infections. UTX-deficient T cells showed decreased expression of interleukin-6 receptor-α and other Tfh cell-related genes that were associated with increased H3K27 methylation. Additionally, Turner Syndrome subjects, who are predisposed to chronic ear infections, had reduced UTX expression in immune cells and decreased circulating CD4(+) CXCR5(+) T cell frequency. Thus, we identify a critical link between UTX in T cells and immunity to infection.
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Cook
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA; Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA.
authors.forename: Karl B
authors.initials: KB
authors.lastname: Shpargel
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA; Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Starmer
authors.affiliation: Department of Pediatrics, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA.
authors.forename: Fatima
authors.initials: F
authors.lastname: Whitfield-Larry
authors.affiliation: Department of Pediatrics, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA.
authors.forename: Bridget
authors.initials: B
authors.lastname: Conley
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA.
authors.forename: Denise E
authors.initials: DE
authors.lastname: Allard
authors.affiliation: Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Rager
authors.affiliation: Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fry
authors.affiliation: Department of Pediatrics, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA.
authors.forename: Marsha L
authors.initials: ML
authors.lastname: Davenport
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA; Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Magnuson
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA. Electronic address: jwhitmir@email.unc.edu.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Whitmire
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA; Department of Pediatrics, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA. Electronic address: masu@email.unc.edu.
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Su
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D002454:Cell Differentiation; D005260:Female; D018628:Gene Dosage; D005786:Gene Expression Regulation / Q000276:immunology; D020022:Genetic Predisposition to Disease; D056466:Histone Demethylases / Q000172:deficiency* / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D053698:Interleukin-6 Receptor alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D008211:Lymphocyte Cooperation; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology* / Q000472:pathogenicity; D008745:Methylation; D051379:Mice; D018448:Models, Immunological; D009687:Nuclear Proteins / Q000172:deficiency*; D010033:Otitis Media / Q000209:etiology; D011499:Protein Processing, Post-Translational; D054380:Receptors, CXCR5 / Q000032:analysis; D013045:Species Specificity; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000821:virology; D006377:T-Lymphocytes, Helper-Inducer / Q000201:enzymology / Q000276:immunology* / Q000821:virology; D014158:Transcription, Genetic; D014424:Turner Syndrome / Q000150:complications / Q000201:enzymology; D014766:Viremia / Q000276:immunology*; D014774:Virulence; D049951:X Chromosome Inactivation
chemical_list: D000914:Antibodies, Viral; C095085:CXCR5 protein, human; D006657:Histones; D053698:Interleukin-6 Receptor alpha Subunit; D009687:Nuclear Proteins; D054380:Receptors, CXCR5; D056466:Histone Demethylases; C523998:KDM6A protein, human; C111778:Utx protein, mouse