T Follicular Helper Cell-Dependent Clearance of a Persistent Virus Infection Requires T Cell Expression of the Histone Demethylase UTX

Kevin D Cook; Karl B Shpargel; Joshua Starmer; Fatima Whitfield-Larry; Bridget Conley; Denise E Allard; Julia E Rager; Rebecca C Fry; Marsha L Davenport; Terry Magnuson; Jason K Whitmire; Maureen A Su

doi:10.1016/j.immuni.2015.09.002

T Follicular Helper Cell-Dependent Clearance of a Persistent Virus Infection Requires T Cell Expression of the Histone Demethylase UTX

Immunity. 2015 Oct 20;43(4):703-14. doi: 10.1016/j.immuni.2015.09.002. Epub 2015 Sep 29.

Authors

Affiliations

¹ Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA.
² 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.
³ 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.
⁴ Department of Pediatrics, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA.
⁵ Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, 120 Mason Farm Road, Chapel Hill, NC 27599, USA.
⁶ 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.
⁷ 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.
⁸ 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.

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.

Publication types

Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Viral / biosynthesis
Cell Differentiation
Female
Gene Dosage
Gene Expression Regulation / immunology
Genetic Predisposition to Disease
Histone Demethylases / deficiency*
Histone Demethylases / physiology*
Histones / metabolism
Humans
Immunologic Memory
Interleukin-6 Receptor alpha Subunit / biosynthesis
Interleukin-6 Receptor alpha Subunit / genetics
Lymphocyte Cooperation
Lymphocytic Choriomeningitis / immunology
Lymphocytic Choriomeningitis / virology
Lymphocytic choriomeningitis virus / immunology*
Lymphocytic choriomeningitis virus / pathogenicity
Methylation
Mice
Models, Immunological
Nuclear Proteins / deficiency*
Otitis Media / etiology
Protein Processing, Post-Translational
Receptors, CXCR5 / analysis
Species Specificity
T-Lymphocyte Subsets / enzymology
T-Lymphocyte Subsets / immunology*
T-Lymphocyte Subsets / virology
T-Lymphocytes, Helper-Inducer / enzymology
T-Lymphocytes, Helper-Inducer / immunology*
T-Lymphocytes, Helper-Inducer / virology
Transcription, Genetic
Turner Syndrome / complications
Turner Syndrome / enzymology
Viremia / immunology*
Virulence
X Chromosome Inactivation

Substances

Antibodies, Viral
CXCR5 protein, human
Histones
Interleukin-6 Receptor alpha Subunit
Nuclear Proteins
Receptors, CXCR5
Histone Demethylases
KDM6A protein, human
Utx protein, mouse

Associated data

GEO/GSE64969

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding