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

Makoto Kuwahara,Ayako Takemori,Junpei Suzuki,Tatsuya Sawasaki,Masaki Yasukawa,Nobuaki Takemori,Maya Izumoto,Wataru Ise,Kohei Kometani,Toshinori Nakayama,Tomohiro Kurosaki,Osamu Ohara,Saho Maruyama,Mizuki Ochi,Masakatsu Yamashita,Kenta Shinoda,Akira Matsumoto

doi:10.1038/ncomms12596

Abstract

Although Bach2 has 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 find 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.

Highlights

Bach[2] has an important role in regulating the Th2-type immune response, the underlying molecular mechanisms remain unclear
We found that Bach2-deficient naive CD4 T cells produced significant amount of IL-4, IL-5, IL-13 and IFN-g in response to T-cell antigen receptor (TCR) stimulation, whereas the production of IL-2 was comparable to the WT naive CD4 T cells (Fig. 2b)
The data are representative of three-independent experiments with similar results. (e) The results of the enzyme-linked immunosorbent assay (ELISA) for cytokines in the supernatants derived from the lung CD4 T cells stimulated with an immobilized anti-TCR-b monoclonal antibody (mAb) and an anti-CD28 mAb for 16 h. **Po0.01 (Student’s t-test). (f) The levels of histone H3K27 acetylation at the Th2 cytokine gene loci in the lung CD4 T cells were determined using a ChIP-quantitative PCR (qPCR) assay; the results are presented relative to those of input DNA with the s.d. **Po0.01 (Student’s t-test)

Summary

Introduction

Bach[2] has an important role in regulating the Th2-type immune response, the underlying molecular mechanisms remain unclear. The Bach2–Batf complex directly binds to the Batf and Batf[3] gene loci and reduces transcription by interfering with the Batf–Irf[4] 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. We recently demonstrated that senescence-associated secretory phenotype is rapidly induced in Bach2-deficient activated CD4 T cells[23] These findings establish Bach[2] as a key regulator of CD4 T cell-mediated immune homeostasis, the molecular mechanism(s) by which Bach[2] controls the CD4 T cell function and differentiation has yet to be fully elucidated. Batf and Batf[3] are not essential for the interferon-g (IFN-g) expression in Th1 cells

Methods

Results

Conclusion