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

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

Author information

1
Department of Medical Technology, Ehime Prefectural University of Health Sciences, Tobe, Ehime 791-2101, Japan; tyamada@epu.ac.jp yamamasa@m.ehime-u.ac.jp.
2
Department of Infection and Host Defenses, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan.
3
Department of Hematology, Clinical Immunology and Infectious Diseases, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan.
4
Department of Ophthalmology, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan.
5
Department of Immunology, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan.
6
Department of Translational Immunology, Translational Research Center, Ehime University Hospital, Shitsukawa, Toon, Ehime 791-0295, Japan.
7
Division of Integrative Pathophysiology, Department of Proteo-Inovation, Proteo-Science Center, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan; and.
8
Division of Immune Regulation, Department of Proteo-Innovation, Proteo-Science Center, Graduate School of Medicine, Ehime University, Toon, Ehime 791-0295, Japan.
9
Department of Immunology, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan; tyamada@epu.ac.jp yamamasa@m.ehime-u.ac.jp.

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.

PMID:
30626691
DOI:
10.4049/jimmunol.1801083

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