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

Abstract

The AP-1 factor, basic leucine zipper transcription factor, ATF-like (BATF) is important for CD4+ T-helper (Th) 17, Th9 and follicular T helper (Tfh) cell development. However, its precise role in Th2 differentiation and function remains unclear, and the necessity of BATF in non-allergic settings of type-2 immunity has not been explored. Here, we show that in response to parasitic helminths, Batf−/− mice are unable to generate both Tfh and Th2 cells. As a consequence, Batf−/− mice 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 interleukin(IL)-4 and IL-13. In contrast to Th17 and Th9 cell subsets where BATF binds directly to promoter and enhancer regions to regulate cytokine expression, our results show that BATF is significantly enriched at Rad50 hypersensitivity sites (RHS) 6 and 7 of the locus control region (LCR) 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 have been 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 BATF regulates type-2 cytokine production through its modification of the Th2 LCR.

Notch signaling represents an important checkpoint between follicular T-helper and canonical T-helper 2 cell fate

“…Intestinal worm burden, lung eosinophilia, and serum IgE were assessed nine days post infection ( Figure 1 ). In this model, defects in lung eosinophilia and helminth clearance are reflective of impaired Th2-mediated peripheral immunity, while defects in IgE production signify a defect in Tfh-mediated, type-2 humoral responses 6 , 21 . Similar to wild-type mice, IL4 4get CD4 cre Notch1/2 fl/fl mice mounted a productive type-2 response in the periphery, as worms were cleared from the intestine and significant eosinophilia was observed in the lung ( Figure 1a, b ).…”

“…BCL6, BATF, IRF4, and cMaf all play important roles in Tfh cell differentiation 21 - 26 . Many of these factors also have been suggested to play a role in IL-4 expression by Tfh cells 21 , 22 .…”

Regulation of IgE by T follicular helper cells

“…These data led to a model in which Th2 cells may selectively utilize GATA3 and thereby produce IL‐4, ‐5, and ‐13, whereas Tfh cells rely on BATF for isolated IL‐4 production. However, BATF has been shown more recently to regulate IL‐4 production in Th2 cells, demonstrating that its Il4 regulatory activity is not specific to Tfh cells as previously argued …”

“…However, BATF has been shown more recently to regulate IL-4 production in Th2 cells, demonstrating that its Il4 regulatory activity is not specific to Tfh cells as previously argued. 105,106 Although not considered canonical Tfh TFs, multiple studies have since observed that Tfh cells can co-express other lineage TFs such as T-bet and GATA3 along with BCL6 and make cytokines such as IFN or IL-13 during particular type 1 or 2 immune responses. 15,88,[107][108][109][110] Our recent analysis of single-cell RNA-sequencing of Tfh cells induced to the allergen Alternaria alternata showed that IL-13 + IL-4 + Tfh13 cells expressed high levels of Gata3 whereas the IL-4 + Tfh2 cells did not.…”

Molecular Control of Follicular Helper T cell Development and Differentiation

“…BATF does not impair IL-4 in Th2 cells but only Tfh cells ( 61 ). However, other studies show that the loss of Batf impairs IL-4 production in both Tfh and Th2 cells ( 66 , 67 ).…”