BATF is Required for Treg Homeostasis and Stability to Prevent Autoimmune Pathology

Abstract

Regulatory T (Treg) cells are inevitable to prevent deleterious immune responses to self and commensal microorganisms. Treg function requires continuous expression of the transcription factor (TF) FOXP3 and is divided into two major subsets: resting (rTregs) and activated (aTregs). Continuous T cell receptor (TCR) signaling plays a vital role in the differentiation of aTregs from their resting state, and in their immune homeostasis. The process by which Tregs differentiate, adapt tissue specificity, and maintain stable phenotypic expression at the transcriptional level is still inconclusivei. In this work, the role of BATF is investigated, which is induced in response to TCR stimulation in naïve T cells and during aTreg differentiation. Mice lacking BATF in Tregs developed multiorgan autoimmune pathology. As a transcriptional regulator, BATF is required for Treg differentiation, homeostasis, and stabilization of FOXP3 expression in different lymphoid and non‐lymphoid tissues. Epigenetically, BATF showed direct regulation of Treg‐specific genes involved in differentiation, maturation, and tissue accumulation. Most importantly, FOXP3 expression and Treg stability require continuous BATF expression in Tregs, as it regulates demethylation and accessibility of the CNS2 region of the Foxp3 locus. Considering its role in Treg stability, BATF should be considered an important therapeutic target in autoimmune disease.

Deciphering the developmental trajectory of tissue-resident Foxp3+ regulatory T cells

“…In particular, a K199del mutation situated in the zing-finger (ZF) domain or mutations R51Q or C168Y in the N-terminal regions are prone to generating symptoms of enteropathy and skin disorders, while a R337Q mutation in the DNA-binding Fork-head domain can, in addition to these symptoms, lead to the development of diabetes mellitus ( 101 ). In addition, a murine model mimicking an A384 mutation in Foxp3 was shown to specifically impair T REG cell function in the periphery, directly impairing the ability of Foxp3 to recognize target genes and altering BATF expression ( 102 ), a key transcription factor required for TR-T REG generation ( 103 ). As such, the ability of Foxp3 to interact with multiple partners is required to preserve the functional integrity of T REG cells in peripheral tissues.…”

“…Delacher and colleagues identified a BATF-dependent transcriptional program that drives, notably, the expression of the IL-33 receptor ST2 ( 120 ), a receptor specifically found in TR-T REG ( 17 ). A T REG -specific BATF deficiency in mice ( Foxp3 CRE Batf fl/fl ; BATF -/- ), results in a multiorgan autoimmune disease with death initiating at 6 weeks of age ( 103 ). BATF -/- T REG cells fail to accumulate in the lungs, colon, liver, and spleen, and display reduced chromatin accessibility to genes involved in T REG survival in tissue, including Gata3 , Irf4, Ikzf4 , Ets1 and Icos ( 103 ).…”

“…A T REG -specific BATF deficiency in mice ( Foxp3 CRE Batf fl/fl ; BATF -/- ), results in a multiorgan autoimmune disease with death initiating at 6 weeks of age ( 103 ). BATF -/- T REG cells fail to accumulate in the lungs, colon, liver, and spleen, and display reduced chromatin accessibility to genes involved in T REG survival in tissue, including Gata3 , Irf4, Ikzf4 , Ets1 and Icos ( 103 ). In addition, Foxp3 CRE Batf fl/fl mice generate exT REG cells that lose T REG -associated genes ( Ctla4, Tgfb1, Foxp3 ) and adopt inflammatory genes ( Rorc, Il6ra, Stat3 ) ( 103 ).…”

“…BATF -/- T REG cells fail to accumulate in the lungs, colon, liver, and spleen, and display reduced chromatin accessibility to genes involved in T REG survival in tissue, including Gata3 , Irf4, Ikzf4 , Ets1 and Icos ( 103 ). In addition, Foxp3 CRE Batf fl/fl mice generate exT REG cells that lose T REG -associated genes ( Ctla4, Tgfb1, Foxp3 ) and adopt inflammatory genes ( Rorc, Il6ra, Stat3 ) ( 103 ). Specifically, ATAC-seq of murine BATF WT and BATF -/- T REG cells reveals BATF acts as a chromatin regulator, facilitating the expression of TR-T REG -associated genes, including Ctla4 , Icos , Gata3 , and Irf4 , and preserving the demethylated state of the CNS2 region of Foxp3 ( 103 ), positioning BATF as the epigenetic guardian of T REG cells as they undergo their differentiation into specialized memory T REG cells.…”

CRISPR-GEM: A Novel Machine Learning Model for CRISPR Genetic Target Discovery and Evaluation

“…3B). Top scoring SRGN and high ranking CD48 accomplish this through interactions with BATF, a transcription factor that is required for Treg differentiation, homeostasis and function [43][44][45][46] . FOX3P upregulation also occurs through downstream of LTB, TSC22D3 genes.…”