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Retinoic Acid Enhances Foxp3 Induction Indirectly by Relieving Inhibition from CD4(+)CD44(hi) Cells.

ABSTRACT: CD4(+)Foxp3(+) regulatory T (Treg) cells originate primarily from thymic differentiation, but conversion of mature T lymphocytes to Foxp3 positivity can be elicited by several means, including in vitro activation in the presence of TGF-beta. Retinoic acid (RA) increases TGF-beta-induced expression of Foxp3, through unknown molecular mechanisms. We showed here that, rather than enhancing TGF-beta signaling directly in naive CD4(+) T cells, RA negatively regulated an accompanying population of CD4(+) T cells with a CD44(hi) memory and effector phenotype. These memory cells actively inhibited the TGF-beta-induced conversion of naive CD4(+) T cells through the synthesis of a set of cytokines (IL-4, IL-21, IFN-gamma) whose expression was coordinately curtailed by RA. This indirect effect was evident in vivo and required the expression of the RA receptor alpha. Thus, cytokine-producing CD44(hi) cells actively restrain TGF-beta-mediated Foxp3 expression in naive T cells, and this balance can be shifted or fine-tuned by RA.

ORGANISM(S): Mus musculus

PROVIDER: GSE13306 | GEO | 2008/11/16

SECONDARY ACCESSION(S): PRJNA109885

REPOSITORIES: GEO

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Retinoic Acid Enhances Foxp3 Induction Indirectly by Relieving Inhibition from CD4(+)CD44(hi) Cells.

Project description:CD4(+)Foxp3(+) regulatory T (Treg) cells originate primarily from thymic differentiation, but conversion of mature T lymphocytes to Foxp3 positivity can be elicited by several means, including in vitro activation in the presence of TGF-beta. Retinoic acid (RA) increases TGF-beta-induced expression of Foxp3, through unknown molecular mechanisms. We showed here that, rather than enhancing TGF-beta signaling directly in naive CD4(+) T cells, RA negatively regulated an accompanying population of CD4(+) T cells with a CD44(hi) memory and effector phenotype. These memory cells actively inhibited the TGF-beta-induced conversion of naive CD4(+) T cells through the synthesis of a set of cytokines (IL-4, IL-21, IFN-gamma) whose expression was coordinately curtailed by RA. This indirect effect was evident in vivo and required the expression of the RA receptor alpha. Thus, cytokine-producing CD44(hi) cells actively restrain TGF-beta-mediated Foxp3 expression in naive T cells, and this balance can be shifted or fine-tuned by RA. All gene expression profiles were obtained from highly purified T cell populations sorted by flow cytometry. To reduce variability, cells from multiple mice were pooled for sorting, and replicates were generated for essentially all groups. RNA from 0.5-3 x 105 cells was amplified, labeled, and hybridized to Affymetrix M430v2 microarrays. Raw data were preprocessed with the RMA algorithm in GenePattern, and averaged expression values were used for analysis.

2008-11-16 | E-GEOD-13306 | biostudies-arrayexpress

in vitro differentiated Th0, Th17, and Tr1 cells

Project description:Gene expression profiling of in vitro differentiated murine Th cell subsets. Flow cytometrically sorted naive Th cells (CD4+ CD44- Foxp3-) were polyclonally stimulated in vitro for 3 days using 4 µg/ml plate-bound antibody to CD3 (145-2C11) and 2 µg/ml soluble antibody to CD28 (PV-1). Th0 cells were cultured in the absence of exogenous cytokines. Th17 cells were differentiated with 50 ng/ml IL-6 plus 0.5 ng/ml TGF-β. Tr-1 cells were differentiated with 100 ng/ml IL-27 plus 0.5 ng/ml TGF-β.

2014-03-20 | GSE56021 | GEO

TGF-beta/Smad3-dependent gene expression analysis in naive CD4 T cells

Project description:Investigation of transcript level modulation in unstimulated and TGF-beta treated (with or without superimposed T-cell receptor and CD28 stimulation) naive CD4 T cells from wild type or Smad3-deficient littermate mice. Smad3 is a critical signaling molecule and transcription factor downstream of TGF-beta and mediates several of the TGF-beta dependent tolerogenic effects in T cells. This study was undertaken to unveil the transcriptionnal program controled by the TGF-b/Smad3 axis. Microarray study using RNA recovered after 6 hours of culture in either serum free media, serum-free media + TGF-beta (2.5ng/ml) or serum-free media + TGF-beta and anti-CD3e and anti-CD28 stimulation (3 conditions). Naive CD4 T cells (TCRb+, CD4+, CD62L+ and CD44-) were sorted from either wild type or Smad3 deficient littermates and submitted to the 3 culture conditions. Three biological replicates were obtained (each from at least 2 different mice). Thus a total of 18 Nimblegen 365K chip were used.

2012-08-31 | E-GEOD-40494 | biostudies-arrayexpress

Furin deficiency efect on T cells

Project description:Analysis of T-cells lacking the proprotein convertase furin. Proprotein convertases promote the proteolytic maturation of proproteins. Furin is induced in activated T-cells. Results provide insight into the function of furin in T-cells. CD4+CD62L+CD44- naive, CD4+CD62L-CD44+ memory and CD4+CD25+FoxP3+ regulatory T cells were isolated from Fur flox/flox and CD4 cre Fur flox/flox mice. Naive T cells were activated via TCR. Total RNA was extracted from all cells and hybridized to Affymetrix microarrays.

2015-08-05 | E-GEOD-67884 | biostudies-arrayexpress

in vitro differentiated Th0, Th17, and Tr1 cells

Project description:Gene expression profiling of in vitro differentiated murine Th cell subsets. Flow cytometrically sorted naive Th cells (CD4+ CD44- Foxp3-) were polyclonally stimulated in vitro for 3 days using 4 Âµg/ml plate-bound antibody to CD3 (145-2C11) and 2 Âµg/ml soluble antibody to CD28 (PV-1). Th0 cells were cultured in the absence of exogenous cytokines. Th17 cells were differentiated with 50 ng/ml IL-6 plus 0.5 ng/ml TGF-Î². Tr-1 cells were differentiated with 100 ng/ml IL-27 plus 0.5 ng/ml TGF-Î². Five biological replicates per Th subset (Th0, Th17, Tr1)

2014-03-20 | E-GEOD-56021 | biostudies-arrayexpress

Transcription profiling of activated CD4+ T cells from A1.RAGnull mice retrovirally transduced with TGF beta or FoxP3

Project description:To assess the effect of TGF beta or FoxP3 retroviral transduction on transcripts expressed by activated CD4 T cells from A1.RAGnull mice.

2007-12-21 | E-MEXP-1157 | biostudies-arrayexpress

CD44 acts as a co-receptor to confer cell type-specific enhancement of signaling and regulatory T cell induction by TGM-1, a helminth parasite mimic of TGF

Project description:Long-lived parasites evade host immunity through highly evolved molecular strategies. The murine intestinal helminth, Heligmosomoides polygyrus, suppresses the host immune system through release of an immunoregulatory TGF-β mimic, TGM-1, which is a divergent member of the CCP (Sushi) protein family. TGM-1 comprises 5 domains, of which domains 1-3 (D1/2/3) bind mammalian TGFβ receptors, acting on T cells to induce Foxp3+ regulatory T cells; however, the roles of domains 4 and 5 (D4-5) remain unknown. We noted that a truncated TGM-1, lacking these domains, showed reduced potency. Combination of D1/2/3 and D4/5 as separate proteins did not restore full potency, suggesting that a physical linkage is required, and that these domains may not deliver an independent signal. Co-precipitation from cells treated with biotinylated D4/5, followed by mass spectrometry, identified the cell surface protein CD44 as a co-receptor for TGM-1. Both full-length and D4/5 bound strongly to a range of primary cells and cell lines, while D1/2/3 binding was only marginally detectable. Ectopic expression of CD44 in non responding cells conferred responsiveness, while specific genetic depletion of CD44 abolished the enhancement effect of D4/5, and ablated the ability of full-length TGM-1 to bind to cell surfaces. Moreover, CD44-deficient T cells showed attenuated induction of Foxp3 by full-length TGM-1, to levels similar to D1/2/3. Hence, a parasite protein known to bind two host cytokine receptor subunits has evolved a third receptor specificity, which serves to raise the avidity and cell type-specific potency of TGF-β signaling in mammalian cells.

2023-10-24 | PXD037799 | Pride

The kinases MEKK2 and MEKK3 regulate Transforming Growth Factor-β-mediated helper T cell differentiation

Project description:Mitogen-activated protein kinases (MAPKs) are key mediators of the T cell receptor (TCR) signals but their roles in T helper (Th) cell differentiation are unclear. Here we showed that the MAPK kinase kinases MEKK2 (encoded by Map3k2) and MEKK3 (encoded by Map3k3),negatively regulated transforming growth factor-beta (TGF-beta)-mediated Th cell differentiation.Map3k2-/-Map3k3Lck-Cre/- mice showed an abnormal accumulation of regulatory T (Treg) and Th17 cells in the periphery, consistent with Map3k2-/-Map3k3Lck-Cre/- naïve CD4+ T cells’ differentiation into Treg and Th17 cells with a higher frequency than wild-type (WT) cells after TGF-beta stimulation in vitro. In addition, Map3k2-/-Map3k3Lck-Cre/- mice developed more severe experimental autoimmune encephalomyelitis. Map3k2-/-Map3k3Lck-Cre/- T cells exhibited impaired phosphorylation of the SMAD2 and SMAD3 proteins at their linker regions, which negatively regulated the TGF-beta responses in T cells. Thus, the crosstalk between TCR-induced MAPK and the TGF-beta signaling pathways is important in regulating Th cell differentiation. CD4+CD62L-CD44+ cells were FACS sorted from C57BL/6 Lck-Cre MEKK2 KO MEKK3F/-(dKO) or C57BL/6 WT mice

2011-02-02 | E-GEOD-26987 | biostudies-arrayexpress

TGF-beta/Smad3-dependent gene expression analysis in naive CD4 T cells

2012-08-31 | GSE40494 | GEO

Neonatal T helper 17 responses are skewed towards an immunoregulatory interleukin-22 phenotype

Project description:We report broad developmental differences in gene expression profiles between neonatal (term) and adult naive CD4 T cells, resulting in non-stereotypic Th17 differentiation responses to TGF-beta.

2020-12-31 | GSE135467 | GEO

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