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

Abstract

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.

Keywords: CD8(+) T cell function; LCMV; antiviral defense; epigenetics; histone demethylation; persistent infection.