Foxa1 and Foxa2 in thymic epithelial cells (TEC) regulate medullary TEC and regulatory T-cell maturation

Lau, Ching‐In; Yánez, Diana C.; Solanki, Anisha; Papaioannou, Eleftheria; Saldaña, José Ignacio; Crompton, Tessa

doi:10.1016/j.jaut.2018.07.009

Cited by 14 publications

(12 citation statements)

References 42 publications

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“…CD4 + CD25 – T cells and CD4 + CD25 + Treg cells from WT and Gli2ΔC2 spleens of Oxa-treated mice were FACS-sorted. WT CD4 + T cells were first stained with CFSE and then cocultured with Tregs at 1:1 and 1:4 ratios as described (77) for 4 days.…”

Section: Methodsmentioning

confidence: 99%

Sonic Hedgehog signaling limits atopic dermatitis via Gli2-driven immune regulation

Papaioannou

Yánez

Ross

et al. 2019

Journal of Clinical Investigation

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Hedgehog (Hh) proteins regulate development and tissue homeostasis, but their role in atopic dermatitis (AD) remains unknown. We found that on induction of mouse AD, Sonic Hedgehog (Shh) expression in skin and Hh pathway action in skin T cells were increased. Shh signaling reduced AD pathology and the levels of Shh expression determined disease severity. Hh-mediated transcription in skin T cells in AD-induced mice increased Treg populations and their suppressive function through increased active transforming growth factor–β (TGF-β) in Treg signaling to skin T effector populations to reduce disease progression and pathology. RNA sequencing of skin CD4 + T cells from AD-induced mice demonstrated that Hh signaling increased expression of immunoregulatory genes and reduced expression of inflammatory and chemokine genes. Addition of recombinant Shh to cultures of naive human CD4 + T cells in iTreg culture conditions increased FOXP3 expression. Our findings establish an important role for Shh upregulation in preventing AD, by increased Gli-driven, Treg cell–mediated immune suppression, paving the way for a potential new therapeutic strategy.

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Section: Methodsmentioning

confidence: 99%

Sonic Hedgehog signaling limits atopic dermatitis via Gli2-driven immune regulation

Papaioannou

Yánez

Ross

et al. 2019

Journal of Clinical Investigation

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“…Conditional deletion of Foxa1 and Foxa2 from TEC increased the proportion of medullary TEC, but reduced cell-surface MHCII expression on TEC, leading to a smaller thymus with a reduction in conventional CD4 T-cell differentiation but an increase in the CD4 Treg population (25). In the thymus, Foxa1 and Foxa2 are also expressed in developing T-cells, and Foxa2 is a transcriptional target of Shh signalling after pre-TCR signal transduction (12,26).…”

Section: Development • Accepted Manuscriptmentioning

confidence: 99%

The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during thymocyte positive selection

et al. 2021

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During positive selection at the transition from CD4+CD8+ double-positive (DP) to single-positive (SP) thymocyte, TCR signalling results in appropriate MHC restriction and signals for survival and progression. We show that the pioneer transcription factors Foxa1 and Foxa2 are required to regulate RNA splicing during positive selection of mouse T cells and that Foxa1 and Foxa2 have overlapping/compensatory roles. Conditional deletion of both Foxa1 and Foxa2 from DP thymocytes reduced positive selection and development of CD4SP, CD8SP and peripheral naïve CD4+ T cells. Foxa1 and Foxa2 regulated the expression of many genes encoding splicing factors and regulators, including Mbnl1, H1f0, Sf3b1, Hnrnpa1, Rnpc3, Prpf4b, Prpf40b and Snrpd3. Within the positively selecting CD69+DP cells, alternative RNA splicing was dysregulated in the double Foxa1/Foxa2 conditional knockout, leading to >850 differentially used exons. Many genes important for this stage of T-cell development (Ikzf1-3, Ptprc, Stat5a, Stat5b, Cd28, Tcf7) and splicing factors (Hnrnpab, Hnrnpa2b1, Hnrnpu, Hnrnpul1, Prpf8) showed multiple differentially used exons. Thus, Foxa1 and Foxa2 are required during positive selection to regulate alternative splicing of genes essential for T-cell development, and, by also regulating splicing of splicing factors, they exert widespread control of alternative splicing.

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“…All of these transcription factor binding sites have been shown to potentially alter T cells and/or affect subset differentiation, and some have been implicated in autoimmunity. For example, FOXA2 is has been shown to regulate T cell differentiation in the thymus to promote positive selection of CD4 + T cells while downregulating Tregs (63). FOXA2 modulated the production of Th2 cytokines in mouse atopic dermatitis model via its action on T regs (64).…”

Section: Discussionmentioning

confidence: 99%

Continuous Developmental and Early Life Trichloroethylene Exposure Promoted DNA Methylation Alterations in Polycomb Protein Binding Sites in Effector/Memory CD4+ T Cells

et al. 2019

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Trichloroethylene (TCE) is an industrial solvent and drinking water pollutant associated with CD4 + T cell-mediated autoimmunity. In our mouse model, discontinuation of TCE exposure during adulthood after developmental exposure did not prevent immunotoxicity. To determine whether persistent effects were linked to epigenetic changes we conducted whole genome reduced representation bisulfite sequencing (RRBS) to evaluate methylation of CpG sites in autosomal chromosomes in activated effector/memory CD4 + T cells. Female MRL+/+ mice were exposed to vehicle control or TCE in the drinking water from gestation until ~37 weeks of age [postnatal day (PND) 259]. In a subset of mice, TCE exposure was discontinued at ~22 weeks of age (PND 154). At PND 259, RRBS assessment revealed more global methylation changes in the continuous exposure group vs. the discontinuous exposure group. A majority of the differentially methylated CpG regions (DMRs) across promoters, islands, and regulatory elements were hypermethylated (~90%). However, continuous developmental TCE exposure altered the methylation of 274 CpG sites in promoters and CpG islands. In contrast, only 4 CpG island regions were differentially methylated (hypermethylated) in the discontinuous group. Interestingly, 2 of these 4 sites were also hypermethylated in the continuous exposure group, and both of these island regions are associated with lysine 27 on histone H3 (H3K27) involved in polycomb complex-dependent transcriptional repression via H3K27 tri-methylation. CpG sites were overlapped with the Open Regulatory Annotation database. Unlike the discontinuous group, continuous TCE treatment resulted in 129 DMRs including 12 unique transcription factors and regulatory elements; 80% of which were enriched for one or more polycomb group (PcG) protein binding regions (i.e., SUZ12, EZH2, JARID2, and MTF2). Pathway analysis of the DMRs indicated that TCE primarily altered the methylation of genes associated with regulation of cellular metabolism and cell signaling. The results demonstrated that continuous developmental exposure to TCE differentially methylated binding sites of PcG proteins in effector/memory CD4 + cells. There were minimal yet potentially biologically significant effects that occurred when exposure was discontinued. These results point toward a novel mechanism by which chronic developmental TCE exposure may alter terminally differentiated CD4 + T cell function in adulthood.

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Foxa1 and Foxa2 in thymic epithelial cells (TEC) regulate medullary TEC and regulatory T-cell maturation

Cited by 14 publications

References 42 publications

Sonic Hedgehog signaling limits atopic dermatitis via Gli2-driven immune regulation

Sonic Hedgehog signaling limits atopic dermatitis via Gli2-driven immune regulation

The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during thymocyte positive selection

Continuous Developmental and Early Life Trichloroethylene Exposure Promoted DNA Methylation Alterations in Polycomb Protein Binding Sites in Effector/Memory CD4+ T Cells

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