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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.
AuthorsKevin 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
JournalImmunity (Immunity) Vol. 43 Issue 4 Pg. 703-14 (Oct 20 2015) ISSN: 1097-4180 [Electronic] United States
PMID26431949 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 Elsevier Inc. All rights reserved.
Chemical References
  • Antibodies, Viral
  • CXCR5 protein, human
  • Histones
  • Interleukin-6 Receptor alpha Subunit
  • Nuclear Proteins
  • Receptors, CXCR5
  • Histone Demethylases
  • KDM6A protein, human
  • Utx protein, mouse
Topics
  • Animals
  • Antibodies, Viral (biosynthesis)
  • Cell Differentiation
  • Female
  • Gene Dosage
  • Gene Expression Regulation (immunology)
  • Genetic Predisposition to Disease
  • Histone Demethylases (deficiency, physiology)
  • Histones (metabolism)
  • Humans
  • Immunologic Memory
  • Interleukin-6 Receptor alpha Subunit (biosynthesis, genetics)
  • Lymphocyte Cooperation
  • Lymphocytic Choriomeningitis (immunology, virology)
  • Lymphocytic choriomeningitis virus (immunology, pathogenicity)
  • Methylation
  • Mice
  • Models, Immunological
  • Nuclear Proteins (deficiency)
  • Otitis Media (etiology)
  • Protein Processing, Post-Translational
  • Receptors, CXCR5 (analysis)
  • Species Specificity
  • T-Lymphocyte Subsets (enzymology, immunology, virology)
  • T-Lymphocytes, Helper-Inducer (enzymology, immunology, virology)
  • Transcription, Genetic
  • Turner Syndrome (complications, enzymology)
  • Viremia (immunology)
  • Virulence
  • X Chromosome Inactivation

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