Histone H3K27 demethylase negatively controls the memory formation of Ag-stimulated CD8+ T cells

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 Utx knockout (Utx KO) mice to determine the role of Utx in CD8+ T cells. Wild-type (WT) and Utx KO mice were infected with Listeria monocytogenes expressing OVA to analyze the immune response of Ag-specific CD8+ T cells upon primary and secondary infections. There was no significant differences in the primary expansion of Ag-specific CD8+ T cells between WT and Utx KO mice. However, Utx deficiency resulted in an increased secondary expansion of Ag-specific CD8+ T cells. Adoptive transferred Utx KO CD8+ T cells resulted in increased numbers of CD127hi KLRG1lo memory precursors in the primary expansion and larger numbers of memory cells. We observed a decreased gene expression of effector-associated transcription factors, including Prdm1 encoding Blimp1, in Utx KO CD8+ T cells upon primary infection. We confirmed that the tri-methylation level of histone H3K27 in the Prdm1 gene loci in the Utx KO cells was higher than in the WT cells. The treatment of CD8+ T cells with Utx-cofactor a-ketoglutarate hampered the memory formation, while Utx-inhibitor GSK-J4 enhanced the memory formation and increased the secondary expansion 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 expression of genes, including Prdm1. Based on these findings, we identified a critical link between Utx and the differentiation of Ag-stimulated CD8+ T cells upon infection Overall design: Profile of histone H3K27me3 in WT and Utx KO CD8 T cells