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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

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

The contained self-reactive peripheral T cell repertoire: size, diversity and cellular composition

Project description:To further characterize the self-reactive T cell population and determine if there are sub-compartments within the naïve T cell pool that are more likely to respond in the absence of Treg cell-mediated control, we focused on CD5. CD5 is a membrane protein that is associated with the TCR and its expression is correlated with higher signaling intensity, presumably due to higher TCR self-MHC/peptide affinity, during positive selection. FACS was used to purify three distinct populations of naïve CD4+ T cells from the bottom, middle and top 10 percent based on CD5 expression; CD5low, CD5int and CD5high.

2015-08-04 | GSE70154 | GEO

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

Project description:Regulatory T (Treg) cells suppress the development of inflammatory disease, but our knowledge of transcriptional regulators that control this function remains incomplete. Here we show that expression of Id2 and Id3 in Treg cells was required to suppress development of fatal inflammatory disease. We found that T cell antigen receptor (TCR)-driven signaling initially decreased the abundance of Id3, which led to the activation of a follicular regulatory T (TFR) cell–specific transcription signature. However, sustained lower abundance of Id2 and Id3 interfered with proper development of TFR cells. Depletion of Id2 and Id3 expression in Treg cells resulted in compromised maintenance and localization of the Treg cell population. Thus, Id2 and Id3 enforce TFR cell checkpoints and control the maintenance and homing of Treg cells. Treg mRNA profiles in lymph node from 3-week-old Id2fl/flId3fl/fl;Foxp3Cre/Cre (Id2 Id3 double-knockout) and control mice are generated by deep sequencing.

2014-06-29 | E-GEOD-57682 | biostudies-arrayexpress

Tconv and Treg gene expression and repertoire analysis of ZAC mice

Project description:Autoimmune diseases, such as rheumatoid arthritis (RA), are believed to be caused, in part, by a defect in the selection of T cells. Developing T cells undergo a process known as “negative selection” where self-derived proteins are presented to the cells; those that react to the self-peptides are either eliminated, or develop into regulatory T cells (Tregs), which suppress immune responses by conventional T cells (Tconvs). In order to study self-reactive T cell receptors (TCRs), and their likely target antigens, we performed single cell repertoire analysis in ZAC mice with impaired TCR signaling. We sequenced TCR and transcriptomes of Treg and Tconv single cells from arthritic ZAC mice spleen (n=2). We discovered a cluster of pro-inflammatory Th17 Tconv cells in ZAC spleens that was absent in WT mice. ZAC Th17 TCRs showed clonal expansion. Different mice had different TCR sequences, which is expected.

2022-11-22 | GSE180015 | GEO

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

2014-06-29 | GSE57682 | GEO

Unstableregulatory and autoreactive effector T cells in patients with FOXP3 mutations

Project description:Studies of the monogenic autoimmune disease immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) have elucidated the essential function of the transcription factor FOXP3 and thymic-derived regulatory T cells (Tregs) in controlling peripheral tolerance. However, the presence and the source of autoreactive T cells in IPEX remain undetermined. Here, we investigated how FOXP3 deficiency affects the T cell receptor (TCR) repertoire and Treg stability in vivo and compared T cell abnormalities in patients with IPEX to those in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED). To study Tregs independently of their phenotype and to analyze T cell autoreactivity, we combined Treg-specific demethylation region analyses, single-cell multi-omic profiling, and bulk TCR sequencing. We found that patients with IPEX, unlike patients with APECED, have expanded autoreactive T cells originating from both autoreactive effector T cells (Teffs) and Tregs. In addition, a fraction of the expanded Tregs lost their phenotypic and functional markers including CD25 and often also FOXP3. Functional experiments with CRISPR/Cas9-mediated FOXP3 knock-out Treg and Tregs from patients with IPEX indicated that the patients’ Tregs gain a Th2 skewed Teff-like function, which is consistent with immune dysregulation observed in these patients. Analyses of FOXP3 mutation-carrier mothers and a patient with IPEX after hematopoietic stem cell transplantation, indicated that Tregs expressing non-mutated FOXP3 prevent the accumulation of autoreactive Teffs and unstable Tregs. Collectively, we describe Treg instability and Teff autoreactivity in patients with IPEX. These findings could be directly used for diagnostic and prognostic purposes and for monitoring the effects of immunomodulatory treatments.

2023-12-20 | GSE247274 | GEO

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

Genome-wide analysis of chromatin accessibility in developing thymic Treg cells

Project description:We analyzed open chromatin regions in thymic Treg cells, their immediate precursors (CD25+ Foxp3-), and mature and semi-mature CD4 single positive cells. We wished to understand which chromatin regions become accessible in response to TCR-stimulation and then Foxp3 expression as Treg cells develop.

2019-08-19 | GSE134366 | GEO

TCR sequencing of Treg and Tconv subsets from murine spleen

Project description:While unique subsets of Treg cells have been described in some non-lymphoid tissues, their relationship to Treg cells in secondary lymphoid organs and circulation remains unclear. We have identified a recirculating and highly suppressive effector Treg cell subset that expresses the α2 integrin, CD49b, and exhibits a unique tissue distribution. We used TCR sequencing to ask whether CD49b+ activated Treg cells and CD49b− activated Treg cells represent stable states of Treg cell differentiation instructed by distinct TCR repertoires. We did not find a pattern of clonotypes that was specific to either subset, suggesting that essentially all CD49b− Treg cells could give rise to CD49b+ cells. These results shed light on the identity and development of a functionally potent subset of mature effector Treg cells that recirculate through and survey peripheral tissues.

2018-10-22 | GSE121147 | GEO

Expression data from murine Treg subsets defined by CD103 and ICOS expression before and after activation by an in vitro CD4 T cell suppression assay

Project description:Regulatory T cells (Treg) are pivotal for the maintenance of peripheral tolerance by controlling self-reactive, chronic and homeostatic T cell responses. We now report that the increase in Treg suppressive function observed in lymphopenic mice correlates with the degree of lymphopenia and is caused by a higher frequency of a novel subpopulation of CD103posICOSpos cells among peripheral Treg that differentially express multiple Treg signature genes.

2015-03-08 | GSE57922 | GEO

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