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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE62532 | GEO | 2014/10/21

SECONDARY ACCESSION(S): PRJNA264341

REPOSITORIES: GEO

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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

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Id2 and Id3 maintain the regulatory T cell pool to suppress inflammatory disease

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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

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