The activating protein 1 transcription factor basic leucine zipper transcription factor, ATF-like (BATF), regulates lymphocyte- and mast cell-driven immune responses in the setting of allergic asthma

Abstract

Background: Mice without the basic leucine zipper transcription factor, ATF-like (BATF) gene (Batf(-/-)) lack TH17 and follicular helper T cells, which demonstrates that Batf is a transcription factor important for T- and B-cell differentiation.

Objective: In this study we examined whether BATF expression would influence allergic asthma.

Methods: In a cohort of preschool control children and children with asthma, we analyzed BATF mRNA expression using real-time PCR in PBMCs. In a murine model of allergic asthma, we analyzed differences in this allergic disease between wild-type, Batf transgenic, and Batf(-/-) mice.

Results: In the absence of corticosteroid treatment, children with recurrent asthma have a significant increase in BATF mRNA expression in their PBMCs. Batf(-/-) mice display a significant reduction in the pathophysiologic responses seen in asthmatic wild-type littermates. Moreover, we discovered a decrease in IL-3 production and IL-3-dependent mast cell development in Batf(-/-) mice. By contrast, IFN-γ was induced in lung CD4(+) and CD8(+) T cells. Intranasal delivery of anti-IFN-γ antibodies induced airway hyperresponsiveness and inflammation in wild-type but not in Batf(-/-) mice. Transgenic overexpression of Batf under the control of the CD2 promoter/enhancer augmented lung inflammation and IgE levels in the setting of experimental asthma.

Conclusion: BATF is increased in non-steroid-treated asthmatic children. Targeting BATF expression resulted in amelioration of the pathophysiologic responses seen in children with allergic asthma, and BATF has emerged as a novel target for antiasthma interventions.

Keywords: AHR; ATF; Activating transcription factor; Airway hyperresponsiveness; BAL; BALF; BATF; BMMC; Basic leucine zipper transcription factor, ATF-like; Bone marrow–derived mast cell; Bronchoalveolar lavage; Bronchoalveolar lavage fluid; Enhanced pause; Forkhead box protein 3; Foxp3; IRF4; Interferon regulatory factor 4; MCh; Methacholine; OVA; Ovalbumin; P(enh); Phospho–signal transducer and activator of transcription 5; RORγt; Regulatory T; Retinoic acid–related orphan receptor γt; SCF; STAT; Signal transducer and activator of transcription; Stem cell factor; T cells; T(H)17; T(H)2; T-bet; T-box transcription factor; Treg; asthma; mast cells; pSTAT5.