Tet DNA demethylase is required for plasma cell differentiation by controlling expression levels of IRF4

Kentaro Fujii, Shinya Tanaka, Takanori Hasegawa, Masashi Narazaki, Atsushi Kumanogoh, Haruhiko Koseki, Tomohiro Kurosaki, Wataru Ise

研究成果: Contribution to journalArticle査読

1 被引用数 (Scopus)

抄録

Antibodies produced by plasma cells are critical for protection from infection. It has been demonstrated that global epigenetic modification, such as changes in DNA methylation, occurs during differentiation of plasma cells from B cells. However, the precise mechanisms by which DNA methylation controls plasma cell differentiation are not fully understood. We examined the effect of deficiency of DNA demethylases, Tet2 and Tet3, on B-cell activation and plasma cell differentiation, by generating conditional Tet2/3 double-KO (Tet dKO) B cells. We found that Tet dKO B cells failed to differentiate into plasma cells upon immunization with antigens. Tet dKO B cells proliferated normally and were capable of generating cells with IRF4int, but not with IRF4hi, the majority of which were CD138+ plasma cells. IRF4 overexpression rescued the defect of Tet dKO B cells in plasma cell differentiation, suggesting that Tet2/3-dependent high IRF4 expression is required for plasma cell differentiation. We identified CpG sites in the Irf4 locus that were demethylated specifically in plasma cells and in a Tet2/3-dependent manner. Our results suggest that Tet2/3-dependent demethylation of these CpG sites is dispensable for initial IRF4 expression but is essential for high IRF4 expression which is prerequisite for plasma cell differentiation.

本文言語英語
ページ(範囲)683-690
ページ数8
ジャーナルInternational immunology
32
10
DOI
出版ステータス出版済み - 2020

All Science Journal Classification (ASJC) codes

  • 免疫アレルギー学
  • 免疫学

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