Histone H3K27 Demethylase Negatively Controls the Memory Formation of Antigen-Stimulated CD8+ T Cells

Abstract

Although the methylation status of histone H3K27 plays a critical role in CD4⁺ T cell differentiation and its function, the role of Utx histone H3K27 demethylase in the CD8⁺ T cell-dependent immune response remains unclear. We therefore generated T cell-specific <i>Utx</i> ^flox/flox Cd4-Cre Tg (<i>Utx</i> KO) mice to determine the role of Utx in CD8⁺ T cells. Wild-type (WT) and <i>Utx</i> KO mice were infected with <i>Listeria monocytogenes</i> expressing OVA to analyze the immune response of Ag-specific CD8⁺ T cells. There was no significant difference in the number of Ag-specific CD8⁺ T cells upon primary infection between WT and <i>Utx</i> KO mice. However, <i>Utx</i> deficiency resulted in more Ag-specific CD8⁺ T cells upon secondary infection. Adoptive transfer of <i>Utx</i> KO CD8⁺ T cells resulted in a larger number of memory cells in the primary response than in WT. We observed a decreased gene expression of effector-associated transcription factors, including <i>Prdm1</i> encoding Blimp1, in <i>Utx</i> KO CD8⁺ T cells. We confirmed that the trimethylation level of histone H3K27 in the <i>Prdm1</i> gene loci in the <i>Utx</i> KO cells was higher than in the WT cells. The treatment of CD8⁺ T cells with Utx-cofactor α-ketoglutarate hampered the memory formation, whereas Utx inhibitor GSK-J4 enhanced the memory formation in WT CD8⁺ T cells. These data suggest that Utx negatively controls the memory formation of Ag-stimulated CD8⁺ T cells by epigenetically regulating the gene expression. Based on these findings, we identified a critical link between Utx and the differentiation of Ag-stimulated CD8⁺ T cells.