BATF Modulates the Th2 Locus Control Region and Regulates CD4+ T Cell Fate during Antihelminth Immunity

• Published in: The Journal of immunology (1950) Vol. 197; no. 11; pp. 4371 - 4381
• Main Authors: Bao, Katherine, Carr, Tiffany, Wu, Jianxuan, Barclay, William, Jin, Jingxiao, Ciofani, Maria, Reinhardt, R Lee
• Format: Journal Article
• Language: English
• Published: United States 01.12.2016
• Subjects: Animals; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - immunology; Basic-Leucine Zipper Transcription Factors - genetics; Basic-Leucine Zipper Transcription Factors - immunology; Epigenesis, Genetic - immunology; Locus Control Region - immunology; Mice; Mice, Knockout; Strongylida Infections - genetics; Strongylida Infections - immunology; Strongylida Infections - pathology; Th2 Cells - immunology; Th2 Cells - pathology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1601371

The AP-1 factor basic leucine zipper transcription factor, ATF-like (BATF) is important for CD4 Th17, Th9, and follicular Th cell development. However, its precise role in Th2 differentiation and function remains unclear, and the requirement for BATF in nonallergic settings of type-2 immunity has not been explored. In this article, we show that, in response to parasitic helminths, Batf mice are unable to generate follicular Th and Th2 cells. As a consequence, they fail to establish productive type-2 immunity during primary and secondary infection. Batf CD4 T cells do not achieve type-2 cytokine competency, which implies that BATF plays a key role in the regulation of IL-4 and IL-13. In contrast to Th17 and Th9 cell subsets in which BATF binds directly to promoter and enhancer regions to regulate cytokine expression, our results show that BATF is significantly enriched at Rad50 hypersensitivity site (RHS)6 and RHS7 of the locus control region relative to AP-1 sites surrounding type-2 cytokine loci in Th2 cells. Indeed, Batf CD4 T cells do not obtain permissive epigenetic modifications within the Th2 locus, which were linked to RHS6 and RHS7 function. In sum, these findings reveal BATF as a central modulator of peripheral and humoral hallmarks of type-2 immunity and begin to elucidate a novel mechanism by which it regulates type-2 cytokine production through its modification of the Th2 locus control region.