Transcriptomic analysis of Tregs from RelB-dDC mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE134779 | GEO | 2019/09/11
REPOSITORIES: GEO
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Project description:Transcriptomic analysis of Tregs from RelB-dDC mice
| PRJNA556427 | ENA
Project description:Thymic medullary epithelial cell (mTEC) expression of the autoimmune regulator AIRE, and of tissue-specific antigens, is controlled by members of the non-canonical NF-kB signalling pathway, including RelB and NF-kB2. Of the genes in this pathway, RelB-/- mice develop a particularly severe multi-organ autoimmune syndrome, resembling Foxp3-deficiency. RelB-/- mice have medullary atrophy and few mTECs but the mechanism is unknown. We show that RelB is required for expression of medullary chemokines and mTEC AIRE, selection of a diverse peripheral T cell repertoire, and for peripheral Foxp3+ Treg function. Vβ families of T cells infiltrating diseased peripheral organs and thymic Treg were similarly skewed. Surprisingly, medullary atrophy results from intra-thymic granulocyte infiltration, consequent upon the Th2-mediated autoimmune disease. Dominant tolerance corrects thymic inflammatory disease and loss of thymic function. We demonstrate a reversible RelB-dependent inflammatory mechanism for loss of central tolerance associated with medullary atrophy. Thymi from 4 RelB+/- mice and 3 RelB-/- mice were profiled by microarays
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Project description:Thymic-derived natural T regulatory cells (nTregs) are characterized by functional and phenotypic heterogeneity. Recently, a small fraction of peripheral Tregs have been shown to express Klrg1, but it remains unclear the extent Klrg1 defines a unique Treg subset. Here we show that Klrg1+ Tregs represent a terminally differentiated Treg subset derived from Klrg1- Tregs. This subset is a recent antigen-responsive and a highly activated short-lived Treg population that expresses enhanced levels of Treg suppressive molecules and that preferentially resides within mucosal tissues. The development of Klrg1+ Tregs also requires extensive IL-2R signaling. This activity represents a distinct function for IL-2, independent from its contribution to Treg homeostasis and competitive fitness. These and other properties are analogous to terminally differentiated short-lived CD8+ T effector cells. Our findings suggest that an important pathway driving antigen-activated conventional T lymphocytes also operates for Tregs. Gene expression analysis was performed of this and other Treg subsets based on expression of CD62L, CD69, and Klrg1 to define the molecular properties of Klrg1+ Tregs and its relationship to other Treg subsets found in the peripheral immune tissues. Mice were euthanized, spleen cell preparations were made, and each Treg subset was isolated by FACS cell sorting. RNA was immediately prepared for processing.
2012-08-06 | E-GEOD-36527 | biostudies-arrayexpress
Project description:Gene-profiling of Tregs across inbred strains. There is a wide inter-individual range in the frequency of FoxP3+ Treg cells, but little is known about the underlying genetic or epigenetic mechanisms. We explored this issue accross inbred strains of mice. During this study, we established the gene expression profiles of Treg cells from the various inbred strains of mice. For each inbred strain of mice, CD4+ TCRb+ CD25hi Treg cells (50k) from 9w old male (Jackson laboratory) were double sorted into Trizol. For BM Treg, cells were triple-sorted. Top 50% among CD25high cells were selected to ensure high Foxp3+ purity (over 99%). 2 biological replicates per condition. RNA was amplified, labeled and hybridized to Affymetrix Mouse Gene 1.0 ST Arrays (Expression Analysis).
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Project description:Gene-profiling of Tregs across inbred strains. There is a wide inter-individual range in the frequency of FoxP3+ Treg cells, but little is known about the underlying genetic or epigenetic mechanisms. We explored this issue accross inbred strains of mice. During this study, we established the gene expression profiles of Treg cells from the various inbred strains of mice.
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Project description:Thymic medullary epithelial cell (mTEC) expression of the autoimmune regulator AIRE, and of tissue-specific antigens, is controlled by members of the non-canonical NF-kB signalling pathway, including RelB and NF-kB2. Of the genes in this pathway, RelB-/- mice develop a particularly severe multi-organ autoimmune syndrome, resembling Foxp3-deficiency. RelB-/- mice have medullary atrophy and few mTECs but the mechanism is unknown. We show that RelB is required for expression of medullary chemokines and mTEC AIRE, selection of a diverse peripheral T cell repertoire, and for peripheral Foxp3+ Treg function. Vβ families of T cells infiltrating diseased peripheral organs and thymic Treg were similarly skewed. Surprisingly, medullary atrophy results from intra-thymic granulocyte infiltration, consequent upon the Th2-mediated autoimmune disease. Dominant tolerance corrects thymic inflammatory disease and loss of thymic function. We demonstrate a reversible RelB-dependent inflammatory mechanism for loss of central tolerance associated with medullary atrophy.
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Project description:Thymic-derived natural T regulatory cells (nTregs) are characterized by functional and phenotypic heterogeneity. Recently, a small fraction of peripheral Tregs have been shown to express Klrg1, but it remains unclear the extent Klrg1 defines a unique Treg subset. Here we show that Klrg1+ Tregs represent a terminally differentiated Treg subset derived from Klrg1- Tregs. This subset is a recent antigen-responsive and a highly activated short-lived Treg population that expresses enhanced levels of Treg suppressive molecules and that preferentially resides within mucosal tissues. The development of Klrg1+ Tregs also requires extensive IL-2R signaling. This activity represents a distinct function for IL-2, independent from its contribution to Treg homeostasis and competitive fitness. These and other properties are analogous to terminally differentiated short-lived CD8+ T effector cells. Our findings suggest that an important pathway driving antigen-activated conventional T lymphocytes also operates for Tregs. Gene expression analysis was performed of this and other Treg subsets based on expression of CD62L, CD69, and Klrg1 to define the molecular properties of Klrg1+ Tregs and its relationship to other Treg subsets found in the peripheral immune tissues.
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Project description:Gene expression profile of dendritic cells (DC) of mesenteric lymph node (mLN) and lamina propria of small intestine (SI-LP) of control mice and mice lacking RelB expression in DCs at steady state, four days and 14 days after infection with Heligmosomoides polygyrus bakeri (Hpb) Dendritic cells (DCs) are crucial for initiating protective immune responses and have also been implicated in the generation and regulation of Foxp3+ regulatory T cells (Tregs). Specific DC subsets or DC-intrinsic pathways regulate immunity against pathogens but also tolerance to harmless antigens derived from food or microbiota at barrier sites, but underlying mechanisms in the intestinal tract remain poorly defined. Here, we provide evidence that the alternative NF-B family member RelB controls a defined transcriptional program in migratory DC subsets of mesenteric lymph nodes and the small intestinal lamina propria. Functionally, ablation of RelB in dendritic cells result in increased Foxp3+ Treg cell numbers but decreased RORt peripheral Treg cell numbers maintained even under inflammatory conditions. Single-cell RNA-sequencing revealed a complete RelB dependency for the differentiation of cryptopatches and isolated lymphoid follicles-associated DCs (CIA-DCs) in the lamina propria of the small intestine. In addition, we show a RelB-dependent signature of migratory DCs in mesenteric lymph nodes favoring DC-Treg cell interaction by affecting the expression of chemokines (Ccl22, Ccl17), migration behavior (Cd63), co-stimulatory molecule (Cd80, Cd40, Cd200, Tnfsf4), and tolerance-related integrin (Itgb5, Itgb8) expression. Functionally, increased Treg cell numbers in DC-specific RelB knockout animals did not show any risk of increased reactions in a model of food allergy but instead prevented protective Th2 immune responses in the intestines after infection with Heligmosomoides polygyrus bakeri despite their slight steady-state type 2 immune bias. This protection was dependent on elevated Treg cell frequencies during primary infection as a result of bystander immune tolerance. Thus, RelB expression in conventional DCs acts as a rheostat to establish a tolerogenic set point that is maintained even during infection and strong type 2 immune conditions and thereby is a key regulator of intestinal homeostasis.
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