Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity.

A contribution of epigenetic modifications to B cell tolerance has been proposed but not directly tested. Here we report that deficiency of ten-eleven translocation (Tet) DNA demethylase family members Tet2 and Tet3 in B cells led to hyperactivation of B and T cells, autoantibody production and lupus-like disease in mice. Mechanistically, in the absence of Tet2 and Tet3, downregulation of CD86, which normally occurs following chronic exposure of self-reactive B cells to self-antigen, did not take place. The importance of dysregulated CD86 expression in Tet2- and Tet3-deficient B cells was further demonstrated by the restriction, albeit not complete, on aberrant T and B cell activation following anti-CD86 blockade. Tet2- and Tet3-deficient B cells had decreased accumulation of histone deacetylase 1 (HDAC1) and HDAC2 at the Cd86 locus. Thus, our findings suggest that Tet2- and Tet3-mediated chromatin modification participates in repression of CD86 on chronically stimulated self-reactive B cells, which contributes, at least in part, to preventing autoimmunity.

Citation

Shinya Tanaka, Wataru Ise, Takeshi Inoue, Ayako Ito, Chisato Ono, Yoshihito Shima, Shuhei Sakakibara, Manabu Nakayama, Kentaro Fujii, Ikuo Miura, Jafar Sharif, Haruhiko Koseki, Pandelakis A Koni, Indu Raman, Quan-Zhen Li, Masato Kubo, Katsunori Fujiki, Ryuichiro Nakato, Katsuhiko Shirahige, Hiromitsu Araki, Fumihito Miura, Takashi Ito, Eiryo Kawakami, Yoshihiro Baba, Tomohiro Kurosaki. Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity. Nature immunology. 2020 Aug;21(8):950-961

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PMID: 32572241

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