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Continuous requirement for the T cell receptor for regulatory T cell function

ABSTRACT: Foxp3+ regulatory T cells (Treg cells) maintain immunological tolerance and their deficiency results in fatal multi-organ autoimmunity. Although heightened T cell receptor (TCR) signaling is critical for the differentiation of Treg cells, the role of TCR signaling in Treg cell function remains largely unknown. Here we demonstrate inducible ablation of the TCR results in Treg cell dysfunction which cannot be attributed to impaired Foxp3 expression, decreased expression of Treg cell signature genes or altered ability to sense and consume interleukin 2. Rather, TCR signaling was required for maintaining the expression of a limited subset of genes comprising 25% of the activated Treg cell transcriptional signature. Our results reveal a critical role for the TCR in Treg cell suppressor capacity. Array expression of Foxp3-CreERT2 CalphaFL/WT mice

ORGANISM(S): Mus musculus

SUBMITTER: Aaron Arvey

PROVIDER: E-GEOD-61077 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Continuous requirement for the TCR in regulatory T cell function.

Levine Andrew G AG Arvey Aaron A Jin Wei W Rudensky Alexander Y AY

Nature immunology 20140928 11

Foxp3(+) regulatory T cells (T(reg) cells) maintain immunological tolerance, and their deficiency results in fatal multiorgan autoimmunity. Although heightened signaling via the T cell antigen receptor (TCR) is critical for the differentiation of T(reg) cells, the role of TCR signaling in T(reg) cell function remains largely unknown. Here we demonstrated that inducible ablation of the TCR resulted in T(reg) cell dysfunction that could not be attributed to impaired expression of the transcription ...[more]

PMID: 25263123

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Continuous requirement for the T cell receptor for regulatory T cell function

Project description:Foxp3+ regulatory T cells (Treg cells) maintain immunological tolerance and their deficiency results in fatal multi-organ autoimmunity. Although heightened T cell receptor (TCR) signaling is critical for the differentiation of Treg cells, the role of TCR signaling in Treg cell function remains largely unknown. Here we demonstrate inducible ablation of the TCR results in Treg cell dysfunction which cannot be attributed to impaired Foxp3 expression, decreased expression of Treg cell signature genes or altered ability to sense and consume interleukin 2. Rather, TCR signaling was required for maintaining the expression of a limited subset of genes comprising 25% of the activated Treg cell transcriptional signature. Our results reveal a critical role for the TCR in Treg cell suppressor capacity.

2014-09-08 | GSE61077 | GEO

Nemo-like kinase drives Foxp3 stability and is critical for maintenance of immune tolerance by regulatory T cells

Project description:The Foxp3 transcription factor is a crucial determinant of both regulatory T (TREG) cell development and their functional maintenance. Appropriate modulation of tolerogenic immune responses therefore requires tight regulation of Foxp3 transcriptional output, and this involves both transcriptional and post-translational regulation. Here, we show that during T cell activation, phosphorylation of Foxp3 in TREG cells can be regulated by a TGFβ Activated Kinase 1 (TAK1)-Nemo Like Kinase (NLK) signaling pathway. NLK interacts with Foxp3 in TREG cells and directly phosphorylates Foxp3 on multiple serine residues. This phosphorylation results in stabilization of Foxp3 protein levels by preventing association with the STUB1 E3-ubiquitin protein ligase, resulting in both reduced ubiquitination and proteasome-mediated degradation. Conditional TREG cell NLK-knockout (NLKTREG) results in decreased TREG cell-mediated immunosuppression in vivo and NLK-deficient TREG cell animals develop more severe experimental autoimmune encephalomyelitis. Our data suggest a molecular mechanism, in which stimulation of TCR-mediated signaling can induce a TAK1-NLK pathway to sustain Foxp3 transcriptional activity through stabilization of protein levels, thereby maintaining TREG cell suppressive function. Pharmacological manipulation of this phosphorylation-ubiquitination axis may provide therapeutic opportunities for regulating TREG cell function, for example during cancer immunotherapy.

2019-09-02 | PXD011164 | Pride

Quantitative Proteomics Reveals Specialized Wiring of Signaling Pathways that Protects Human Regulatory T Cell Identity - 5 populations ex vivo

Project description:Regulatory CD4+ T cells (Tregs) are functionally distinct from conventional CD4+ T cells (Tconvs). To understand Treg identity, we compared by proteomics and transcriptomics human naïve (n) and effector (e)Tregs, Tconvs and transitional FOXP3+ cells. Only 12% of 422 differentially expressed proteins was identified as such at the mRNA level, demonstrating the importance of direct proteome measurement. Fifty-one proteins discriminated Tregs from Tconvs. This common Treg protein signature indicates altered signaling by TCR-, TNF receptor-, NFB-, PI3 kinase/mTOR-, NFAT- and STAT pathways, and unique cell biological and metabolic features. Another protein signature uniquely identified eTregs and revealed active cell division, apoptosis sensitivity and suppression of NFB- and STAT signaling. eTreg fate appears consolidated by FOXP3 outnumbering its partner transcription factors. These features explain why eTregs cannot produce inflammatory cytokines, whereas transitional FOXP3+ cells can. Collectively, our data reveal that Treg identity is defined and protected by uniquely “wired” signaling pathways.

2018-05-18 | PXD005477 | Pride

Quantitative Proteomics Reveals Specialized Wiring of Signaling Pathways that Protects Human Regulatory T Cell Identity - 2 populations in vitro

2018-05-18 | PXD007745 | Pride

Quantitative Proteomics Reveals Specialized Wiring of Signaling Pathways that Protects Human Regulatory T Cell Identity - 6 populations ex vivo

2018-05-18 | PXD007744 | Pride

Foxp3 exploits a preexistent enhancer landscape for regulatory T cell lineage specification [Expression]

Project description:Regulatory T (Treg) cells, whose identity and function are defined by the transcription factor Foxp3, are indispensable for immune homeostasis. It is unclear whether Foxp3 exerts its Treg lineage specification function through active modification of the chromatin landscape and establishment of new enhancers or by exploiting a pre-existing enhancer landscape. Analysis of the chromatin accessibility of Foxp3-bound enhancers in Treg and Foxp3-negative T cells showed that Foxp3 was bound overwhelmingly to pre-accessible enhancers occupied by its cofactors in precursor cells or a structurally related predecessor. Furthermore, the bulk of Foxp3-bound Treg cell enhancers inaccessible in Foxp3- CD4+ cells became accessible upon T cell receptor activation prior to Foxp3 expression with only a small subset associated with several functionally important genes being exclusively Treg cell-specific. Thus, in a late cellular differentiation process Foxp3 defines Treg cell functionality in an “opportunistic” manner by largely exploiting the preformed enhancer network instead of establishing a new enhancer landscape. Array expression. Three cell types with 3-5 replicates each.

2012-09-28 | E-GEOD-40685 | biostudies-arrayexpress

Inflammation induced repression of Foxp3-bound chromatin in regulatory T cells [microarray]

Project description:The transcription factor Foxp3 is indispensable for the ability of regulatory T (Treg) cells to suppress fatal inflammation. Here, we characterized the role of Foxp3 in chromatin remodeling and regulation of gene expression in actively suppressing Treg cells in an inflammatory setting. Although genome-wide Foxp3 occupancy of DNA regulatory elements was similar in resting and in vivo activated Treg cells, Foxp3-bound enhancers were poised for repression only in activated Treg cells. Following activation, Foxp3-bound sites showed reduced chromatin accessibility and selective H3K27 tri-methylation, which was associated with Ezh2 recruitment and downregulation of nearby gene expression. Thus, Foxp3 poises its targets for repression by facilitating formation of repressive chromatin in regulatory T cells upon their activation in response to inflammatory cues. The supplementary file GSE55705_dt_expr.txt is a matrix for Treg expression data from platform GPL1261 that includes co-normalized data from GSE40685. array expression

2014-04-12 | E-GEOD-55705 | biostudies-arrayexpress

Foxo1/3-deficient Treg cells

Project description:Identification of Foxos target genes in Treg cells. Foxo1and Foxo3 are transcription factors of Foxo family. CD4+Foxp3+ Treg cells isolated from wild-type and Foxo1/3-deficient mice were analyzed by global gene expression profiling. Results indicate Foxos regulate expression of a subset of Treg cell signature genes and genes in control of T cell homeostasis, signaling and metabolism. 2 sets wild-type and Foxo1/3-deficient CD4+Foxp3+ Treg cells

2010-09-13 | E-GEOD-21678 | biostudies-arrayexpress

Continuous T cell receptor signals maintain a functional regulatory T cell pool

Project description:During development, thymocytes bearing a moderately self-reactive T cell receptor (TCR) can be selected to become regulatory T (Treg) cells. Several observations suggest that also in the periphery mature Treg cells continuously receive self-reactive TCR signals. However, the importance of this inherent autoreactivity for Treg cell biology remains poorly defined. To address this open question, we genetically ablated the TCR of mature Treg cells in vivo. These experiments revealed that TCR-induced Treg lineage-defining FoxP3 expression and gene hypomethylation were uncoupled from TCR input in mature Treg cells. However, Treg cell homeostasis, cell-type-specific gene expression and suppressive function critically depend on continuous triggering of their TCR. TCRpos (FoxP3+ CD4+ CD25high cells from CM-NM-1F/F FoxP3 I eGFP mice) and TCRneg (FoxP3+ TCRM-bM-^@M-^S CD4+ CD25high cells from Mx-Cre CM-NM-1F/F FoxP3 I eGFP mice) Treg cells were FACS sorted 6 weeks after poly(I:C) injection. Cells from 3-5 mice were pooled for sorting, and 4 replicates for the controls (TCRpos) as well as 5 replicates for the Mx-Cre (TCRneg) mice were generated. mRNA from 3-5 x 105 cells was purified with a RNeasy Micro kit (Qiagen), amplified, labeled and hybridized to Affymetrix M430 V2 microarrays

2014-10-21 | E-GEOD-62532 | biostudies-arrayexpress

Comparison of expression profiles of Foxp3(+)epigenetics(-) T cells, Foxp3(-)epigenetics(+) T cells, and Foxp3(+)epigenetics(+) T cells

Project description:Analysis of Foxp3(+)epigenetics(-) T cells, Foxp3(-)epigenetics(+) T cells, and Foxp3(+)epigenetics(+) T cells. Results indicate regulatory T cell (Treg) ontogenesis requires two independent processes, expression of the transcription factor Foxp3 and establishment of Treg epigenetic programs induced by T cell receptor (TCR) stimulation.

2012-11-05 | GSE25252 | GEO

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