Bach2-Batf interactions control Th2-type immune responses by regulating the IL-4 amplification loop. Bach2-Batf interactions control Th2-type immune responses by regulating the IL-4 amplification loop

Although Bach2 plays an important role in regulating the Th2-type immune response, the underlying molecular mechanisms remain unclear. We herein demonstrate that Bach2 associates with Batf and binds to the regulatory regions of the Th2 cytokine gene loci. The Bach2-Batf complex antagonizes the recruitment of the Batf-Irf4 complex to AP-1 motifs and suppresses Th2 cytokine production. Furthermore, we found that Bach2 regulates the Batf and Batf3 expressions via two distinct pathways. First, Bach2 suppresses the maintenance of the Batf and Batf3 expression through the inhibition of IL-4 production. Second, the Bach2-Batf complex directly binds to the Batf and Batf3 gene loci and reduces transcription by interfering with the Batf-Irf4 complex. These findings suggest that IL-4 and Batf form a positive feedback amplification loop to induce Th2 cell differentiation and the subsequent Th2-type immune response, and Bach2-Batf interactions are required to prevent an excessive Th2 response. Overall design: Global patterns of H3K27ac level at the Th2 cytokine gene loci in the WT and Bach2-deficient naïve cells cultured under neutral or Th2 conditions (ChIP-seq analysis). Global patterns of Bach2 binding at the Th2 cytokine gene loci in the WT and Bach2-deficient naïve cells cultured under neutral conditions (ChIP-seq analysis). Gene expression in Bach2 WT-Th (Bach2 WT-Th (-)), Bach2 KO-Th (Bach2 KO-Th (-)), restimulated Bach2 WT-Th (Bach2 WT Th (+)) and re-stimulated Bach2 KO-Th (Bach2 KO Th (+)).