Histone H3K27 Demethylase Negatively Controls the Memory Formation of Antigen-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 Cd4-Cre Tg ( KO) mice to determine the role of Utx in CD8 T cells. Wild-type (WT) and KO mice were infected with 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 KO mice. However, deficiency resulted in more Ag-specific CD8 T cells upon secondary infection. Adoptive transfer of 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 encoding Blimp1, in KO CD8 T cells. We confirmed that the trimethylation level of histone H3K27 in the gene loci in the 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.