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 (T_H2) immune responses as patients with allergic diseases. However, the molecular mechanisms underlying Bcl6-directed regulation of T_H2 cytokine genes remain unclear. We identified multiple Bcl6/STAT binding sites (BSs) in T_H2 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_H2 cells. Contrarily, in memory T_H2 (mT_H2) cells derived from adaptively transferred T_H2 effectors, Bcl6 outcompeted STAT5 for binding to T_H2 cytokine gene loci, particularly Interleukin4 (Il4) loci, and attenuated GATA binding protein 3 (GATA3) binding to highly conserved intron enhancer regions in mT_H2 cells. Bcl6 suppressed cytokine production epigenetically in mT_H2 cells to negatively tune histone acetylation at T_H2 cytokine gene loci, including Il4 loci. In addition, IL-33, a pro-T_H2 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_H2 cells but no altered production in newly differentiated T_H2 cells. Use of a murine asthma model that generates high levels of pro-T_H2 cytokines, such as IL-33, suggested that the suppressive function of Bcl6 in mT_H2 cells is abolished in severe asthma. These findings indicate a role of the interaction between T_H2-promoting factors and Bcl6 in promoting appropriate IL-4 production in mT_H2 cells and suggest that chronic allergic diseases involve the T_H2-promoting factor-mediated functional breakdown of Bcl6, resulting in allergy exacerbation.