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

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

doi:10.1038/s41590-020-0700-y

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

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 ArakiFumihito Miura, Takashi Ito, Eiryo Kawakami, Yoshihiro Baba, Tomohiro Kurosaki

Immunology

Research output: Contribution to journal › Article › peer-review

56 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	950-961
Number of pages	12
Journal	Nature immunology
Volume	21
Issue number	8
DOIs	https://doi.org/10.1038/s41590-020-0700-y
State	Published - Aug 1 2020

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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Tanaka, S., Ise, W., Inoue, T., Ito, A., Ono, C., Shima, Y., Sakakibara, S., Nakayama, M., Fujii, K., Miura, I., Sharif, J., Koseki, H., Koni, P. A., Raman, I., Li, Q. Z., Kubo, M., Fujiki, K., Nakato, R., Shirahige, K., ... Kurosaki, T. (2020). Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity. Nature immunology, 21(8), 950-961. https://doi.org/10.1038/s41590-020-0700-y

Tanaka, S, Ise, W, Inoue, T, Ito, A, Ono, C, Shima, Y, Sakakibara, S, Nakayama, M, Fujii, K, Miura, I, Sharif, J, Koseki, H, Koni, PA, Raman, I, Li, QZ, Kubo, M, Fujiki, K, Nakato, R, Shirahige, K, Araki, H, Miura, F, Ito, T, Kawakami, E, Baba, Y & Kurosaki, T 2020, 'Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity', Nature immunology, vol. 21, no. 8, pp. 950-961. https://doi.org/10.1038/s41590-020-0700-y

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title = "Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity",

abstract = "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.",

author = "Shinya Tanaka and Wataru Ise and Takeshi Inoue and Ayako Ito and Chisato Ono and Yoshihito Shima and Shuhei Sakakibara and Manabu Nakayama and Kentaro Fujii and Ikuo Miura and Jafar Sharif and Haruhiko Koseki and Koni, {Pandelakis A.} and Indu Raman and Li, {Quan Zhen} and Masato Kubo and Katsunori Fujiki and Ryuichiro Nakato and Katsuhiko Shirahige and Hiromitsu Araki and Fumihito Miura and Takashi Ito and Eiryo Kawakami and Yoshihiro Baba and Tomohiro Kurosaki",

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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

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

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