Transcriptional regulator Bhlhe40 works as a cofactor of T-bet in the regulation of IFN-γ production in iNKT cells

Masatoshi Kanda, Hiroyuki Yamanaka, Satoshi Kojo, Yuu Usui, Hiroaki Honda, Yusuke Sotomaru, Michishige Harada, Masaru Taniguchi, Nao Suzuki, Tatsuya Atsumi, Haruka Wada, Muhammad Baghdadi, Ken Ichiro Seino

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35 Citations (Scopus)


Invariant natural killer T (iNKT) cells are a subset of innate-like T cells that act as important mediators of immune responses. In particular, iNKT cells have the ability to immediately produce large amounts of IFN-γ upon activation and thus initiate immune responses in various pathological conditions. However, molecular mechanisms that control IFN-γ production in iNKT cells are not fully understood. Here, we report that basic helix-loop-helix transcription factor family, member e40 (Bhlhe40), is an important regulator for IFN-γ production in iNKT cells. Bhlhe40 is highly expressed in stage 3 thymic iNKT cells and iNKT1 subsets, and the level of Bhlhe40 mRNA expression is correlated with Ifng mRNA expression in the resting state. Although Bhlhe40-deficient mice show normal iNKT cell development, Bhlhe40-deficient iNKT cells show significant impairment of IFN-γ production and antitumor effects. Bhlhe40 alone shows no significant effects on Ifng promoter activities but contributes to enhance T-box transcription factor Tbx21 (T-bet)-mediated Ifng promoter activation. Chromatin immunoprecipitation analysis revealed that Bhlhe40 accumulates in the T-box region of the Ifng locus and contributes to histone H3-lysine 9 acetylation of the Ifng locus, which is impairedwithout T-bet conditions. These results indicate that Bhlhe40 works as a cofactor of T-bet for enhancing IFN-γ production in iNKT cells.

Original languageEnglish
Pages (from-to)E3394-E3402
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number24
Publication statusPublished - Jun 14 2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General


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