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

J Immunol. 2019 Feb 15;202(4):1088-1098. doi: 10.4049/jimmunol.1801083. Epub 2019 Jan 9.

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 Utx flox/flox Cd4-Cre Tg (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. There was no significant difference in the number of Ag-specific CD8+ T cells upon primary infection between WT and Utx KO mice. However, Utx deficiency resulted in more Ag-specific CD8+ T cells upon secondary infection. Adoptive transfer of Utx 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 Prdm1 encoding Blimp1, in Utx KO CD8+ T cells. We confirmed that the trimethylation 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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzazepines / pharmacology
  • CD8 Antigens / immunology*
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Differentiation
  • Histones / immunology*
  • Histones / metabolism
  • Immunologic Memory / drug effects
  • Immunologic Memory / immunology*
  • Jumonji Domain-Containing Histone Demethylases / immunology*
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Pyrimidines / pharmacology

Substances

  • Benzazepines
  • CD8 Antigens
  • GSK-J4
  • Histones
  • Pyrimidines
  • Jumonji Domain-Containing Histone Demethylases
  • Kdm6b protein, mouse