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

1Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. 2Division of Immunology and Genome Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan. 3Division of Molecular Pathology, Research Institute for Biomedical Science, Tokyo University of Science, Noda, Japan. 4Laboratory of Thermo-Therapeutics for Vascular Dysfunction, Osaka University, Suita, Japan. 5Laboratory of Immune Regulation, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan. 6Laboratory of Medical Omics Research, Kazusa DNA Research Institute, Kisarazu, Japan. 7Technology and Development Team for Mouse Phenotype Analysis, RIKEN BioResource Research Center, Tsukuba, Japan. 8Laboratory of Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. 9Advanced Research Departments, Graduate School of Medicine, Chiba University, Chiba, Japan. 10Georgia Cancer Center, Augusta University, Augusta, GA, USA. 11Microarray Core Facility, Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA. 12Laboratory for Cytokine Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. 13Institute of Quantitative Biosciences, The University of Tokyo, Tokyo, Japan. 14Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 15Medical Sciences Innovation Hub Program, RIKEN, Yokohama, Japan. 16Department of Artificial Intelligence Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan. 17Laboratory of Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. ✉e-mail: babay@bioreg.kyushu-u.ac.jp; kurosaki@ifrec.osaka-u.ac.jp Although clonal deletion and receptor editing provide robust systems to eliminate the majority of newly formed self-reactive B cells in bone marrow (BM)1–3, many of these cells still survive in the periphery (~3–10% of peripheral B cells). Normally, however, they exist in a functionally compromised state, called anergy, characterized by desensitized B cell antigen receptor (BCR) signaling induced by chronic exposure to self-antigen and a suppressed ability to undergo plasma cell differentiation4–6. With regard to the B cell-intrinsic mechanisms underlying the maintenance of self-tolerance, it is well known that even modest alterations in B cell signaling thresholds can break tolerance, promoting autoimmunity7. In addition to B cell signaling, the contribution of epigenetic factors has been proposed8,9. One of the previously observed epigenetic abnormalities associated with autoimmune diseases is altered DNA methylation10,11. However, there has been no direct in vivo evidence for involvement of epigenetic mechanisms in B cell tolerance. DNA methyltransferases (DNMTs) add a methyl group to cytosine to generate 5-methylcytosine (5mC). For the reversal of DNA methylation, Tet proteins (Tet1, Tet2 and Tet3) were discovered to act as DNA demethylases by catalyzing the conversion of 5mC in DNA to 5-hydroxymethylcytosine (5hmC) and other intermediate products in the DNA demethylation pathway12,13. In addition to such DNA-demethylating activities, Tet proteins have recently been shown to recruit histone deacetylases (HDACs), thereby mediating transcriptional repression in immune cells14,15. Hence, it is still unclear whether biological processes mediated by Tet proteins result from DNA demethylation, recruitment of chromatin modifiers or both16,17. Here we found that specific deletion of both Tet2 and Tet3 in B cells (bDKO mice) resulted in spontaneous hyperactivation of both B and T cells, autoantibody production and lupus-like disease. Mechanistically, by using a BCR-transgenic model system, we demonstrated that Tet2and Tet3-deficient self-reactive B cells still maintained upregulated CD86, thereby potentiating their ability to activate T cells. Tet2and Tet3-deficient B cells displayed a permissive chromatin state at the Cd86 locus by attenuated accumulation of HDACs. Together, our data suggest that Tet2 and Tet3 contribute to repression of CD86 on self-reactive B cells, which is one of the critical mechanisms to 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
Nature immunology