Critical role of IRF1 and BATF in forming chromatin landscape during type 1 regulatory cell differentiation

Abstract

Type 1 regulatory T (Tr1) cells are induced by interleukin-27 (IL-27) and have critical roles in the control of autoimmunity and resolution of inflammation. Here, we show that the transcription factors IRF1 and BATF are induced early during treatment with IL-27 and are required for the differentiation and function of Tr1 cells in vitro and in vivo. Epigenetic and transcriptional analyses reveal that both transcription factors influence chromatin accessibility and expression of genes required for Tr1 cell function. IRF1 and BATF deficiencies uniquely alter the chromatin landscape, suggesting that these factors serve a pioneering function during Tr1 cell differentiation.

Dynamic transcriptome, accessible genome, and PGR cistrome profiles in the human myometrium

“…69 The motif for TEAD transcription factors is over-represented in PGR binding intervals across all four specimens (Table S12) and expression of TEAD1, TEAD2, TEAD3, and TEAD4 is detected in both NP and TP myometrial tissues (Table S2). The BATF family transcription factors function as a pioneer factor that controls chromatin accessibility 70 and serve as co-regulators for PGR, NR3C1, and AP-1. [71][72][73] The binding motif for BATF, members of the AP-1 superfamily, is among the top enriched motifs within PGR binding regions in all four myometrial samples (Table S12) and BATF, BATF2, and BATF3 are all expressed in both stages of the examined myometrium (Table S2).…”

An endogenous glucocorticoid-cytokine signaling circuit promotes CD8+T cell dysfunction in the tumor microenvironment

“…We further found that some of the GR binding peaks in the Havcr2, Lag3, and IL10 loci overlapped regions of accessible chromatin (based on ATAC-seq) in IL-27-stimulated T cells (Karwacz et al, 2017), which are known to express high levels of these molecules (Chihara et al, 2018) (Figure S6). We therefore tested the effect of GR binding to the cis-regulatory elements in these peaks in the Havcr2, Pdcd1, Lag3, and Tigit loci using luciferase reporter assays.…”

“…We therefore tested the effect of GR binding to the cis-regulatory elements in these peaks in the Havcr2, Pdcd1, Lag3, and Tigit loci using luciferase reporter assays. For IL10, we utilized luciferase reporters of a previously established enhancer element of Il10 -HSS + 2.98 as well as the proximal promoter (-1.5kb) (Karwacz et al, 2017). We transfected the different luciferase reporter constructs along with a Nr3c1 expressing vector or empty vector into 293T cells and treated the cells with glucocorticoid to assay the transactivation capability of the GR.…”

Functional heterogeneity of gut‐resident regulatory T cells

“…Recently, the transcription factors IRF1 and BATF have also been shown to be required for Tr1 cell differentiation. 41 In this review, we discuss the contribution of bacterial and dietary components such as short-chain fatty acids (SCFAs), vitamin A-derived retinoic acid (RA) and dietary antigens to the development, functional maturation and maintenance of intestinal Foxp3 + Treg cells that are crucial for providing tolerogenic microenvironment in the gut.…”

“…IL‐21 secreted by Tr1 cells acts in an autocrine manner to stabilize the Tr1 cell phenotype. Recently, the transcription factors IRF1 and BATF have also been shown to be required for Tr1 cell differentiation 41 …”