科研之友
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摘要
Mice deficient in the transcriptional repressor B-cell CLL/lymphoma 6 (Bcl6) exhibit similar T helper 2 (T(H)2) immune responses as patients with allergic diseases. However, the molecularmechanisms underlying Bcl6-directed regulation of T(H)2 cytokine genes remain unclear. We identified multiple Bcl6/STAT binding sites (BSs) in T(H)2 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 T(H)2 cells. Contrarily, in memory T(H)2 (mT(H)2) cells derived from adaptively transferred T(H)2 effectors, Bcl6 outcompeted STAT5 for binding to T(H)2 cytokine gene loci, particularly Interleukin4 (Il4) loci, and attenuated GATA binding protein 3 (GATA3) binding to highly conserved intron enhancer regions in mT(H)2 cells. Bcl6 suppressed cytokine production epigenetically in mT(H)2 cells to negatively tune histone acetylation at T(H)2 cytokine gene loci, including Il4 loci. In addition, IL-33, a pro-T(H)2 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 mT(H)2 cells but no altered production in newly differentiated T(H)2 cells. Use of a murine asthma model that generates high levels of pro-T(H)2 cytokines, such as IL-33, suggested that the suppressive function of Bcl6 in mT(H)2 cells is abolished in severe asthma. These findings indicate a role of the interaction between T(H)2-promoting factors and Bcl6 in promoting appropriate IL-4 production in mT(H)2 cells and suggest that chronic allergic diseases involve the T(H)2-promoting factor-mediated functional breakdown of Bcl6, resulting in allergy exacerbation.
- 出版日期2017-1-31
- 单位河北医科大学
