Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi.org/10.1093/intimm/dxae028

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.3389/fimmu.2023.1276014

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Event date： 2021.12

Language：Japanese  

Country：Japan  

Event date： 2021.10 - 2021.11

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：On line & at Busan, South Korea   Country：Korea, Republic of  

Event date： 2020.11

Language：English   Presentation type：Oral presentation (general)  

Venue：On line   Country：Japan  

Event date： 2019.12

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：Hamamatsu   Country：Japan  

Event date： 2019.7

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：Fukuoka   Country：Japan  

Immunological tolerance plays a critical role in elimination of self-reactive lymphocytes. Therefore, tolerance break causes an activation of self-reactive lymphocytes, leading to autoimmunity. In peripheral lymphoid organs, a few percent of B cells remain as self-reactive population, although central tolerance robustly removes newly developed self-reactive population They acquire unresponsiveness state after self-antigen recognition and eventually removed from B cell pool, that is called anergy. The previous study demonstrated that the CD86, which is one of the costimulatory molecules for B-T interaction is a key for anergy break. However, the precise molecular mechanism of the peripheral tolerance remains unclear.
Ten-eleven translocation (Tet) play a pleiotropic role in multiple biological events through gene regulation with DNA demethylase activity and HDAC recruitment. Of note, Tet genes are suggested to be implicated with autoimmune diseases by GWAS analysis. However, a role of Tet in B cell tolerance and autoimmunity has been unknown.
B cell-specific Tet2, Tet3 double knock out mice (Cd19 Cre, Tet2f/f, Tet3 f/f; here after Tet bDKO) showed the manifestation of autoimmune diseases such as aberrant immune cell activation, production of autoantibodies and cell infiltration in non-lymphoid organs, suggestive of the bDKO mice as a novel mouse model of autoimmune disorder. The gene expression analysis just before onset of autoimmune response identified CD86 as an only costimulatory molecules whose expression was enhanced in the absence of Tet2/3 in B cells. CD86 blocking in the bDKO mice by neutralizing Ab partially reversed autoimmune condition, suggesting that CD86 is not sufficient but required for aberrant lymphocyte activation in the bDKO mice. Furthermore, deficiency of Tet2/3 caused impaired accumulation of HDAC1/2 on Cd86 gene promoter. In addition, the treatment of activated B cells with HDAC inhibitor enhanced CD86 expression in vitro. These results suggest HDAC-mediated CD86 suppression by Tet in B cells. Furthermore, in tolerance model, Tet-deficiency in autoreactive B cells caused derepression of CD86 and survival advantage. These phenotypes of Tet-deficient B cells may enhance the probability of priming of self-reactive T cells, causing self-reactive B-T interaction. Taken together, Tet2/3 play a crucial role in peripheral B cell tolerance through the epigenetic gene regulation.

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)