Development of chronic allergic responses by dampening Bcl6-mediated suppressor activity in memory T helper 2 cells.

Mice deficient in the transcriptional repressor B-cell CLL/lymphoma 6 (Bcl6) exhibit similar T helper 2 (T2) immune responses as patients with allergic diseases. However, the molecular mechanisms underlying Bcl6-directed regulation of T2 cytokine genes remain unclear. We identified multiple Bcl6/STAT binding sites (BSs) in T2 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 T2 cells. Contrarily, in memory T2 (mT2) cells derived from adaptively transferred T2 effectors, Bcl6 outcompeted STAT5 for binding to T2 cytokine gene loci, particularly Interleukin4 (Il4) loci, and attenuated GATA binding protein 3 (GATA3) binding to highly conserved intron enhancer regions in mT2 cells. Bcl6 suppressed cytokine production epigenetically in mT2 cells to negatively tune histone acetylation at T2 cytokine gene loci, including Il4 loci. In addition, IL-33, a pro-T2 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 mT2 cells but no altered production in newly differentiated T2 cells. Use of a murine asthma model that generates high levels of pro-T2 cytokines, such as IL-33, suggested that the suppressive function of Bcl6 in mT2 cells is abolished in severe asthma. These findings indicate a role of the interaction between T2-promoting factors and Bcl6 in promoting appropriate IL-4 production in mT2 cells and suggest that chronic allergic diseases involve the T2-promoting factor-mediated functional breakdown of Bcl6, resulting in allergy exacerbation.