UTX promotes CD8+ T cell-mediated antiviral defenses but reduces T cell durability

• Published in: Cell reports (Cambridge) Vol. 35; no. 2; p. 108966
• Main Authors: Mitchell, Joseph E., Lund, Makayla M., Starmer, Josh, Ge, Kai, Magnuson, Terry, Shpargel, Karl B., Whitmire, Jason K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.04.2021; Elsevier
• Subjects: Animals; Antigens, CD - genetics; Antigens, CD - immunology; antiviral defense; CD8+ T cell function; Cytotoxicity, Immunologic - genetics; epigenetics; Gene Expression Profiling; Gene Expression Regulation; Hepatitis A Virus Cellular Receptor 2 - genetics; Hepatitis A Virus Cellular Receptor 2 - immunology; Histone Demethylases - deficiency; Histone Demethylases - genetics; Histone Demethylases - immunology; histone demethylation; Histones - genetics; Histones - immunology; Host-Pathogen Interactions - genetics; Host-Pathogen Interactions - immunology; Immunologic Memory - genetics; LCMV; Lymphocytic Choriomeningitis - genetics; Lymphocytic Choriomeningitis - pathology; Lymphocytic choriomeningitis virus - genetics; Lymphocytic choriomeningitis virus - growth & development; Lymphocytic choriomeningitis virus - immunology; Mice; Mice, Inbred C57BL; persistent infection; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - immunology; Signal Transduction; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - virology; Viral Load - genetics; Viral Load - immunology; CD8+ T cell function; LCMV; histone demethylation; persistent infection; antiviral defense; epigenetics; CD8(+) T cell function
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.108966

Persistent virus infections can cause pathogenesis that is debilitating or lethal. During these infections, virus-specific T cells fail to protect due to weakened antiviral activity or failure to persist. These outcomes are governed by histone modifications, although it is unknown which enzymes contribute to T cell loss or impaired function over time. In this study, we show that T cell receptor-stimulated CD8+ T cells increase their expression of UTX (ubiquitously transcribed tetratricopeptide repeat, X chromosome) to enhance gene expression. During chronic lymphocytic choriomeningitis virus (LCMV) infection in mice, UTX binds to enhancers and transcription start sites of effector genes, allowing for improved cytotoxic T lymphocyte (CTL)-mediated protection, independent of its trimethylation of histone 3 lysine 27 (H3K27me3) demethylase activity. UTX also limits the frequency and durability of virus-specific CD8+ T cells, which correspond to increased expression of inhibitory receptors. Thus, UTX guides gene expression patterns in CD8+ T cells, advancing early antiviral defenses while reducing the longevity of CD8+ T cell responses. [Display omitted] •UTX promotes CD8+ T cell-mediated antiviral defenses•UTX increases inhibitory receptor expression and reduces T cell longevity•UTX does not require its H3K27me3 demethylase function to promote gene expression T cells fail to eliminate chronic virus infections due to alterations in gene expression that undermine their activity. In this study, Mitchell et al. identify a histone-modifying enzyme that promotes effector gene expression and CTL activity early on yet reduces T cell survival, leading to infection persistence.