2024-03-28T12:19:42Zhttps://eprints.lib.hokudai.ac.jp/dspace-oai/requestoai:eprints.lib.hokudai.ac.jp:2115/638172022-11-17T02:08:08Zhdl_2115_20058hdl_2115_149Transcriptional regulator Bhlhe40 works as a cofactor of T-bet in the regulation of IFN-γ production in iNKT cellsKanda, MasatoshiYamanaka, HiroyukiKojo, SatoshiUsui, YuuHonda, HiroakiSotomaru, YusukeHarada, MichishigeTaniguchi, MasaruSuzuki, NaoAtsumi, TatsuyaWada, HarukaBaghdadi, MuhammadSeino, Ken-ichironatural killer T cellsbasic helix-loop-helix transcription factorsBhlhe40interferon-γinterferon-gammaT-box transcription factor Tbx21chromatin490Invariant 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 impaired without T-bet conditions. These results indicate that Bhlhe40 works as a cofactor of T-bet for enhancing IFN-γ production in iNKT cells.National Academy of SciencesJournal Articleapplication/pdfapplication/pdfhttp://hdl.handle.net/2115/63817https://eprints.lib.hokudai.ac.jp/dspace/bitstream/2115/63817/2/PNAS113_E3394-SI.pdfhttps://eprints.lib.hokudai.ac.jp/dspace/bitstream/2115/63817/1/PNAS113_E3394.pdf0027-8424AA10808769Proceedings of the National Academy of Sciences of the United States of America11324E3394E34022016-06-14enginfo:doi/10.1073/pnas.1604178113author