Development of chronic allergic responses by dampening Bcl6-mediated suppressor activity in memory T helper 2 cells
| Autor: | Kenji Matsumoto, Toshibumi Taniguchi, Yasutsugu Fukushima, Hirokuni Hirata, Kazuhiro Kurasawa, Lisa Fujimura, Masafumi Arima, Jun Ikari, Haruko Watanabe-Takano, Hirohisa Saito, Masahiko Hatano, Akemi Sakamoto, Susumu Nakae, Takeshi Tokuhisa, Nobuhide Tsuruoka, Hisae Satake, Koichiro Tatsumi, Takashi Ogasawara, Takeshi Fukuda, Kumiya Sugiyama |
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| Rok vydání: | 2017 |
| Předmět: |
Lipopolysaccharides
0301 basic medicine Ovalbumin medicine.medical_treatment Mice Transgenic Biology Histones 03 medical and health sciences Th2 Cells Immune system immune system diseases hemic and lymphatic diseases Interleukin 25 medicine Animals IL-2 receptor Interleukin 4 Mice Inbred BALB C Multidisciplinary Suppressor of cytokine signaling 1 GATA3 Immunoglobulin E BCL6 Asthma 030104 developmental biology Cytokine PNAS Plus Immunology Proto-Oncogene Proteins c-bcl-6 Cytokines |
| Zdroj: | Proceedings of the National Academy of Sciences. 114 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Mice deficient in the transcriptional repressor B-cell CLL/lymphoma 6 (Bcl6) exhibit similar T helper 2 (TH2) immune responses as patients with allergic diseases. However, the molecular mechanisms underlying Bcl6-directed regulation of TH2 cytokine genes remain unclear. We identified multiple Bcl6/STAT binding sites (BSs) in TH2 cytokine gene loci. We found that Bcl6 is modestly associated with the BSs, and it had no significant effect on cytokine production in newly differentiated TH2 cells. Contrarily, in memory TH2 (mTH2) cells derived from adaptively transferred TH2 effectors, Bcl6 outcompeted STAT5 for binding to TH2 cytokine gene loci, particularly Interleukin4 (Il4) loci, and attenuated GATA binding protein 3 (GATA3) binding to highly conserved intron enhancer regions in mTH2 cells. Bcl6 suppressed cytokine production epigenetically in mTH2 cells to negatively tune histone acetylation at TH2 cytokine gene loci, including Il4 loci. In addition, IL-33, a pro-TH2 cytokine, diminished Bcl6's association with loci to which GATA3 recruitment was inversely augmented, resulting in altered IL-4, but not IL-5 and IL-13, production in mTH2 cells but no altered production in newly differentiated TH2 cells. Use of a murine asthma model that generates high levels of pro-TH2 cytokines, such as IL-33, suggested that the suppressive function of Bcl6 in mTH2 cells is abolished in severe asthma. These findings indicate a role of the interaction between TH2-promoting factors and Bcl6 in promoting appropriate IL-4 production in mTH2 cells and suggest that chronic allergic diseases involve the TH2-promoting factor-mediated functional breakdown of Bcl6, resulting in allergy exacerbation. |
| Databáze: | OpenAIRE |
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