TY - JOUR
T1 - Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity
AU - Tanaka, Shinya
AU - Ise, Wataru
AU - Inoue, Takeshi
AU - Ito, Ayako
AU - Ono, Chisato
AU - Shima, Yoshihito
AU - Sakakibara, Shuhei
AU - Nakayama, Manabu
AU - Fujii, Kentaro
AU - Miura, Ikuo
AU - Sharif, Jafar
AU - Koseki, Haruhiko
AU - Koni, Pandelakis A.
AU - Raman, Indu
AU - Li, Quan Zhen
AU - Kubo, Masato
AU - Fujiki, Katsunori
AU - Nakato, Ryuichiro
AU - Shirahige, Katsuhiko
AU - Araki, Hiromitsu
AU - Miura, Fumihito
AU - Ito, Takashi
AU - Kawakami, Eiryo
AU - Baba, Yoshihiro
AU - Kurosaki, Tomohiro
N1 - Funding Information:
We thank A.C. Chan (Genentech) for providing the anti-CD20 monoclonal antibody, K. Rajewsky (Max Delbruck Center for Molecular Medicine) for the Cd19-Cre and μMT mice, C.C. Goodnow (Garvan Institute of Medical Research) for MD4 and ML5 mice, A. O’Garra (Francis Crick Institute) for TCR7 TCR-transgenic mice, T. Shimaoka (Tokyo University of Science) for anti-CD4 monoclonal antibody, H. Fukuyama for assistance with the RNA-seq experiment, A. Baba for plasmid DNA construction, C. Kawai for assistance with experiments, K. Tanaka for assistance with the computational analysis, and N. Yakushiji-Kaminatsui and H. Sugishita for assistance with the ChIP– seq experiment and data processing. We appreciate the technical assistance from the Research Support Center at the Kyushu University Graduate School of Medical Sciences. This research was partially supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED under grant no. JP19am0101103 and JP19am0101105. This work is supported by research grants from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) and AMED (Grant-in-Aid for Scientific Research (S) for T.K., AMED under grant no. 19gm6110004h0003 and Grant-in-Aid for Scientific Research (B) for Y.B. and Grant-in-Aid for Scientific Research (C) for S.T.).
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41590-020-0700-y
DO - 10.1038/s41590-020-0700-y
M3 - Article
C2 - 32572241
AN - SCOPUS:85086788630
SN - 1529-2908
VL - 21
SP - 950
EP - 961
JO - Nature immunology
JF - Nature immunology
IS - 8
ER -