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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.

ORGANISM(S): Mus musculus

PROVIDER: GSE61077 | GEO | 2014/09/08

SECONDARY ACCESSION(S): PRJNA260295

REPOSITORIES: GEO

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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. Array expression of Foxp3-CreERT2 CalphaFL/WT mice

2014-09-08 | E-GEOD-61077 | biostudies-arrayexpress

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 - 6 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. Associated GEO dataset is available at GSE90600.

2018-05-18 | PXD007744 | Pride

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

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

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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

Protein SUMOylation is required for regulatory T cell expansion and function

Project description:Foxp3-expressing regulatory T (Treg) cells are essential regulators in the immune system; molecular mechanisms underlying Treg cell expansion and function are still not well understood. SUMOylation is an important post-translational modification characterized by covalent attachment of SUMO moieties to lysine within proteins. UBC9 is the only E2 conjugation enzyme involved in this process and loss of UBC9 completely impairs the SUMOylation pathway. Here we report that selective deletion ofÂ Ubc9Â within the Treg cell lineage resulted in fatal early-onset autoimmunity as the Foxp3 mutant mice. Ubc9-deficient Treg cells exhibited severe defects in TCR-driven homeostatic proliferation, accompanied by impaired activation and compromised suppressor function. Importantly, TCR-enhanced SUMOylation of IRF4, a critical regulator of Treg cell function downstream of TCR signals, regulates its stability in Treg cells. Our data thus have demonstrated an essential role of SUMOylation in the expansion and function of Treg cells. RNA-seq library was generated using mRNA of CD4+ YFP+ Treg cells sorted from lymph nodes and spleen of Foxp3cre/wtUbc9fl/wt or Foxp3cre/wtUbc9fl/fl mice, each sample contained pooled Treg cells from 5~10 mice.

2016-05-31 | E-GEOD-82031 | 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

Differentiation and homeostasis of effector Treg cells are regulated by inositol polyphosphates modulating Ca2+ influx

Project description:Activated Foxp3+ regulatory T (Treg) cells differentiate into effector Treg (eTreg) cells to maintain peripheral immune homeostasis and tolerance. T cell receptor (TCR)-mediated induction and regulation of store-operated Ca2+ entry (SOCE) is essential for eTreg cell differentiation and function. However, SOCE regulation in Treg cells remains unclear. Here we show that inositol polyphosphate multikinase (IPMK), which generates inositol tetrakisphosphate and inositol pentakisphosphate, is a pivotal regulator of Treg cell differentiation downstream of TCR signaling. IPMK is highly expressed in TCR-stimulated Treg cells and promotes a TCR-induced Treg cell program. IPMK-deficient Treg cells display aberrant T cell activation and impaired differentiation into RORγt+ Treg cells, and tissue-resident Treg cells. Mechanistically, IPMK controls the generation of higher-order inositol phosphates, thereby promoting Ca2+ mobilization and Treg cell effector functions. Our findings identify IPMK as a critical regulator of TCR-mediated Ca2+ influx and highlight the importance of IPMK in Treg cell-mediated immune homeostasis.

2023-05-18 | GSE198960 | GEO

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