JunB Controls Intestinal Effector Programs in Regulatory T Cells

Wheaton, Joshua D.; Ciofani, Maria

doi:10.3389/fimmu.2020.00444

Cited by 11 publications

(9 citation statements)

References 71 publications

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“…A previous study has shown that UBXN1 inhibits pro-inflammatory NF-κB signaling and the interferon response to viral stimuli [ 48 , 49 ]. Furthermore, knockdown of the miR-155-5p target gene JUNB in regulatory T-cells has been shown to lead to increased production of pro-inflammatory cytokines, such as IFN-gamma, in colonic tissue [ 50 , 51 ]. Regulatory T-cell function has previously been shown to be affected in individuals with CeD [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

A Combined mRNA- and miRNA-Sequencing Approach Reveals miRNAs as Potential Regulators of the Small Intestinal Transcriptome in Celiac Disease

Barisani

Panceri

Modderman

et al. 2021

IJMS

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Celiac disease (CeD) is triggered by gluten and results in inflammation and villous atrophy of the small intestine. We aimed to explore the role of miRNA-mediated deregulation of the transcriptome in CeD. Duodenal biopsies of CeD patients (n = 33) and control subjects (n = 10) were available for miRNA-sequencing, with RNA-sequencing also available for controls (n = 5) and CeD (n = 6). Differential expression analysis was performed to select CeD-associated miRNAs and genes. MiRNA‒target transcript pairs selected from public databases that also displayed a strong negative expression correlation in the current dataset (R < −0.7) were used to construct a CeD miRNA‒target transcript interaction network. The network includes 2030 miRNA‒target transcript interactions, including 423 experimentally validated pairs. Pathway analysis found that interactions are involved in immune-related pathways (e.g., interferon signaling) and metabolic pathways (e.g., lipid metabolism). The network includes 13 genes previously prioritized to be causally deregulated by CeD-associated genomic variants, including STAT1. CeD-associated miRNAs might play a role in promoting inflammation and decreasing lipid metabolism in the small intestine, thereby contributing unbalanced cell turnover in the intestinal crypt. Some CeD-associated miRNAs deregulate genes that are also affected by genomic CeD-risk variants, adding an additional layer of complexity to the deregulated transcriptome in CeD.

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Section: Discussionmentioning

confidence: 99%

A Combined mRNA- and miRNA-Sequencing Approach Reveals miRNAs as Potential Regulators of the Small Intestinal Transcriptome in Celiac Disease

Barisani

Panceri

Modderman

et al. 2021

IJMS

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“…We and others have reported that JunB is required for generation of pathogenic Th17 cells that cause autoimmunity, but not for gut-resident homeostatic Th17 cells ( 18 – 20 ). JunB also controls effector Treg homeostasis and immune suppressive functions ( 14 , 15 , 21 – 23 ). Furthermore, JunB promotes expression of cytokines specific to Th2 and Th9 cells ( 17 , 24 ).…”

Section: Introductionmentioning

confidence: 99%

JunB Is Critical for Survival of T Helper Cells

et al. 2022

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Clonal expansion and differentiation of various T helper subsets, such as Th1, Th2, and Th17 cells, depend on a complex of transcription factors, IRF4 and a BATF-containing AP-1 heterodimer. A major BATF heterodimeric partner, JunB, regulates Th17 differentiation, but the role of JunB in other T helper subsets is not well understood. Here we demonstrate that JunB is required for clonal expansion of Th1, Th2 and Th17 cells. In mice immunized with lipopolysaccharide (LPS), papain, or complete Freund’s adjuvant (CFA), which induce predominantly Th1, Th2 and Th17 cells, respectively, accumulation of antigen-primed, Junb-deficient CD4+ T cells is significantly impaired. TCR-stimulated Junb-deficient CD4+ T cells are more sensitive to apoptosis, although they showed largely normal proliferation and cellular metabolism. JunB directly inhibits expression of genes involved in apoptosis, including Bcl2l11 (encoding Bim), by promoting IRF4 DNA binding at the gene locus. Taken together, JunB serves a critical function in clonal expansion of diverse T helper cells by inhibiting their apoptosis.

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“…In view of the universal induction of Batf expression downstream of TCR signaling, the suppression of inducible components of the IL‐2 receptor by Batf may seem counterintuitive for non‐Th17 effector developmental programs, such as Treg and Th1, which are critically dependent on, or amplified by, IL‐2 signaling, respectively. However, while increased CD25 expression has been reported in Batf‐deficient Treg cells (Wheaton & Ciofani, 2020 ) and CD8 T cells (Kurachi et al , 2014 ), suggesting that repression of IL‐2–induced Stat5 may be a common feature of Batf actions across T cell programs, the reduced levels of Batf induced in developing non‐Th17 cells would appear insufficient to deter their IL‐2–dependent programming, consistent with a gradient effect of Batf's actions to impair Il2ra transcription. Moreover, the greatest effect of Batf on restraining CD25 expression appeared to be later in the arc of CD25 expression kinetics, where it may be less impactful for non‐Th17 cells.…”

Section: Discussionmentioning

confidence: 97%

Batf stabilizes Th17 cell development via impaired Stat5 recruitment of Ets1‐Runx1 complexes

et al. 2023

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Although the activator protein‐1 (AP‐1) factor Batf is required for Th17 cell development, its mechanisms of action to underpin the Th17 program are incompletely understood. Here, we find that Batf ensures Th17 cell identity in part by restricting alternative gene programs through its actions to restrain IL‐2 expression and IL‐2‐induced Stat5 activation. This, in turn, limits Stat5‐dependent recruitment of Ets1‐Runx1 factors to Th1‐ and Treg‐cell‐specific gene loci. Thus, in addition to pioneering regulatory elements in Th17‐specific loci, Batf acts indirectly to inhibit the assembly of a Stat5‐Ets1‐Runx1 complex that enhances the transcription of Th1‐ and Treg‐cell‐specific genes. These findings unveil an important role for Stat5‐Ets1‐Runx1 interactions in transcriptional networks that define alternate T cell fates and indicate that Batf plays an indispensable role in both inducing and maintaining the Th17 program through its actions to regulate the competing actions of Stat5‐assembled enhanceosomes that promote Th1‐ and Treg‐cell developmental programs.

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JunB Controls Intestinal Effector Programs in Regulatory T Cells

Cited by 11 publications

References 71 publications

A Combined mRNA- and miRNA-Sequencing Approach Reveals miRNAs as Potential Regulators of the Small Intestinal Transcriptome in Celiac Disease

A Combined mRNA- and miRNA-Sequencing Approach Reveals miRNAs as Potential Regulators of the Small Intestinal Transcriptome in Celiac Disease

JunB Is Critical for Survival of T Helper Cells

Batf stabilizes Th17 cell development via impaired Stat5 recruitment of Ets1‐Runx1 complexes

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