A wave of Thetis cells imparts tolerance to food antigens early in life
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ABSTRACT:
PROVIDER: PRJNA1247582 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33008929.fastq.gz | Fastqsanger.gz | |||
| SRR33008930.fastq.gz | Fastqsanger.gz | |||
| SRR33008931.fastq.gz | Fastqsanger.gz | |||
| SRR33008932.fastq.gz | Fastqsanger.gz | |||
| SRR33008933.fastq.gz | Fastqsanger.gz |
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Project description:In the intestine, peripherally induced regulatory T (pTreg) cells play an essential role in suppressing inflammatory responses to food proteins. However, the identity of the antigen-presenting cells that instruct food-specific pTreg cells is poorly understood. We found that a subset of Thetis cells, TC IV, is required for food-specific pTreg cell differentiation. TC IV were almost exclusively present within mesenteric lymph nodes, suggesting that their presence underlies the phenomenon of oral tolerance. A wave of TC IV differentiation in the periweaning period was associated with a window of opportunity for enhanced pTreg cell generation in response to food antigens. Our findings indicate that TC IV may represent a therapeutic target for the treatment of food-associated allergic and inflammatory diseases.
2025-05-01 | GSE294005 | GEO
Project description:To absorb nutrients and support commensal microbes, the host induces tolerogenic immune responses via peripheral regulatory T cells (pTregs) . Prior studies identified type 1 dendritic cells (cDC1) as initiators of dietary pTregs. However, we now report that food-specific pTreg cells are exclusively induced by the recently identified RORγt APCs and not by cDCs. Instead, our data suggest that pTreg–cDC1 interactions in steady-state limit the expansion of food-specific CD8αβ T cells. This regulation breaks during infection or food poisoning, enabling dietary CD8αβ T cells to expand and acquire effector functions in response to mimicked food antigens. Unlike in typical infections, after the pathogen is cleared, dietary CD8αβ T cells do not expand in response to their corresponding dietary antigens. Thus, we propose that in response to dietary antigens, tolerance is mediated by a circuit of dedicated antigen-presenting cells (APCs) and T cells. When the host is challenged by infection, this circuit permits the transient expansion of protective effector responses without compromising the overall strategy of tolerance that ensures safe food consumption.
2025-05-04 | GSE289339 | GEO
Project description:Tolerance to self- or innocuous foreign antigens is vital for preservation of organismal health. Within the thymus, medullary thymic epithelial cells (mTECs) expressing AutoImmune Regulator, Aire, play a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (Treg) cell development. A second wave of Treg cell differentiation occurs in the periphery, upon exposure to dietary and commensal microbiota derived antigens within the first few weeks of life, yet the cell types responsible for the generation of peripheral Treg (pTreg) cells are not known. Here we identified a new lineage of tolerogenic RORγt+ antigen-presenting cells (APC) with a hybrid dendritic cell (DC)-mTEC phenotype, dubbed Thetis cells (TCs), comprising 4 major sub-groups (TC I-IV), We uncovered a developmental wave of TCs within intestinal lymph nodes during a critical early life window, coincident with the wave of pTreg cell differentiation. While Aire+ TC I and III bore remarkable homology with Aire+ mTECs, including expression of tissue restricted self-antigens, TC IV lacked Aire expression and were enriched for molecules required for pTreg generation, including the TGF-β activating integrin αvβ8. Loss of either MHCII or Itgb8 expression by TCs led to a profound impairment in intestinal pTreg differentiation, with onset of intestinal inflammation. In contrast, MHCII expression by RORγt+ group 3 innate lymphoid cells (ILC3) and classical DCs was neither sufficient nor required for pTreg generation, further implicating TCs as the critical tolerogenic RORγt+ APC. Our studies reveal parallel pathways for establishment of tolerance to self and foreign antigen within the thymus and periphery, marked by involvement of shared cellular and transcriptional programs.
2022-09-06 | GSE174405 | GEO
Project description:Tolerance to self- or innocuous foreign antigens is vital for preservation of organismal health. Within the thymus, medullary thymic epithelial cells (mTECs) expressing AutoImmune Regulator, Aire, play a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (Treg) cell development. A second wave of Treg cell differentiation occurs in the periphery, upon exposure to dietary and commensal microbiota derived antigens within the first few weeks of life, yet the cell types responsible for the generation of peripheral Treg (pTreg) cells are not known. Here we identified a new lineage of tolerogenic RORγt+ antigen-presenting cells (APC) with a hybrid dendritic cell (DC)-mTEC phenotype, dubbed Thetis cells (TCs), comprising 4 major sub-groups (TC I-IV), We uncovered a developmental wave of TCs within intestinal lymph nodes during a critical early life window, coincident with the wave of pTreg cell differentiation. While Aire+ TC I and III bore remarkable homology with Aire+ mTECs, including expression of tissue restricted self-antigens, TC IV lacked Aire expression and were enriched for molecules required for pTreg generation, including the TGF-β activating integrin αvβ8. Loss of either MHCII or Itgb8 expression by TCs led to a profound impairment in intestinal pTreg differentiation, with onset of intestinal inflammation. In contrast, MHCII expression by RORγt+ group 3 innate lymphoid cells (ILC3) and classical DCs was neither sufficient nor required for pTreg generation, further implicating TCs as the critical tolerogenic RORγt+ APC. Our studies reveal parallel pathways for establishment of tolerance to self and foreign antigen within the thymus and periphery, marked by involvement of shared cellular and transcriptional programs.
2022-09-06 | GSE174403 | GEO
Project description:Tolerance to self- or innocuous foreign antigens is vital for preservation of organismal health. Within the thymus, medullary thymic epithelial cells (mTECs) expressing AutoImmune Regulator, Aire, play a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (Treg) cell development. A second wave of Treg cell differentiation occurs in the periphery, upon exposure to dietary and commensal microbiota derived antigens within the first few weeks of life, yet the cell types responsible for the generation of peripheral Treg (pTreg) cells are not known. Here we identified a new lineage of tolerogenic RORγt+ antigen-presenting cells (APC) with a hybrid dendritic cell (DC)-mTEC phenotype, dubbed Thetis cells (TCs), comprising 4 major sub-groups (TC I-IV), We uncovered a developmental wave of TCs within intestinal lymph nodes during a critical early life window, coincident with the wave of pTreg cell differentiation. While Aire+ TC I and III bore remarkable homology with Aire+ mTECs, including expression of tissue restricted self-antigens, TC IV lacked Aire expression and were enriched for molecules required for pTreg generation, including the TGF-β activating integrin αvβ8. Loss of either MHCII or Itgb8 expression by TCs led to a profound impairment in intestinal pTreg differentiation, with onset of intestinal inflammation. In contrast, MHCII expression by RORγt+ group 3 innate lymphoid cells (ILC3) and classical DCs was neither sufficient nor required for pTreg generation, further implicating TCs as the critical tolerogenic RORγt+ APC. Our studies reveal parallel pathways for establishment of tolerance to self and foreign antigen within the thymus and periphery, marked by involvement of shared cellular and transcriptional programs.
2022-09-06 | GSE205066 | GEO
Project description:Tolerance to self- or innocuous foreign antigens is vital for preservation of organismal health. Within the thymus, medullary thymic epithelial cells (mTECs) expressing AutoImmune Regulator, Aire, play a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (Treg) cell development. A second wave of Treg cell differentiation occurs in the periphery, upon exposure to dietary and commensal microbiota derived antigens within the first few weeks of life, yet the cell types responsible for the generation of peripheral Treg (pTreg) cells are not known. Here we identified a new lineage of tolerogenic RORγt+ antigen-presenting cells (APC) with a hybrid dendritic cell (DC)-mTEC phenotype, dubbed Thetis cells (TCs), comprising 4 major sub-groups (TC I-IV), We uncovered a developmental wave of TCs within intestinal lymph nodes during a critical early life window, coincident with the wave of pTreg cell differentiation. While Aire+ TC I and III bore remarkable homology with Aire+ mTECs, including expression of tissue restricted self-antigens, TC IV lacked Aire expression and were enriched for molecules required for pTreg generation, including the TGF-β activating integrin αvβ8. Loss of either MHCII or Itgb8 expression by TCs led to a profound impairment in intestinal pTreg differentiation, with onset of intestinal inflammation. In contrast, MHCII expression by RORγt+ group 3 innate lymphoid cells (ILC3) and classical DCs was neither sufficient nor required for pTreg generation, further implicating TCs as the critical tolerogenic RORγt+ APC. Our studies reveal parallel pathways for establishment of tolerance to self and foreign antigen within the thymus and periphery, marked by involvement of shared cellular and transcriptional programs.
2022-09-06 | GSE205065 | GEO
Project description:Tolerance to dietary antigens is critical to avoid deleterious type 2 immune responses resulting in food allergy (FA) and anaphylaxis. However, the mechanisms resulting in both the maintenance and failure of tolerance to food antigens is poorly understood. Here we demonstrate that the goblet cell-derived resistin-like molecule beta (RELMb) is a critical regulator of oral tolerance. We find that RELMb is abundant in serum in both food allergic patients and mouse models of FA. Deletion of RELMβ protects mice from FA, development of food antigen specific IgE and anaphylaxis. RELMb disrupts food tolerance through modulation of the gut microbiome by suppressing gut Lactobacilli. Tolerance is maintained via local production of indole derivatives driving FA protective RORgt+ regulatory T (Treg) cells via activation of the aryl hydrocarbon receptor (AhR). RELMb antagonism in the peri-weaning period restored oral tolerance and protected genetically prone offspring from developing FA later in life. Together, our data identify RELMb as mediating both a novel gut immune-epithelial circuit regulating tolerance to food antigens, a new mode of innate control of antigen specific adaptive immunity via microbiome editing and targetable candidates in this circuit for prevention and treatment of FA.
2022-12-27 | GSE221462 | GEO
Project description:The intestinal immune system must concomitantly tolerate food and commensals and protect against pathogens. Antigen-presenting cells (APCs) orchestrate these immune responses by presenting luminal antigens to CD4+ T cells and inducing their differentiation into regulatory (pTreg) or inflammatory (Th) subsets. Here, we used LIPSTIC to identify APCs that presented dietary antigens under tolerizing and inflammatory conditions. We show that helminth infections disrupted tolerance proportionally to the reduction in ratio between tolerogenic, including migratory cDC1s and Rorγt+ APCs, and inflammatory APCs, represented primarily by cDC2 subsets. However, the inflammatory subset of cDC2s expanded by helminth infection did not present dietary antigens, thus avoiding diet-specific TH2 cell differentiation. Our data uncover cellular mechanisms by which tolerance to food is induced and can be disrupted by infection.
2024-12-19 | GSE281286 | GEO
Project description:Across the cell cycle, mitochondrial dynamics are regulated by a cycling wave of actin polymerization/depolymerization. In metaphase, this wave induces the assembly of actin comet tails on mitochondria that propel these organelles to drive spatial mixing,resulting in their equitable inheritance by daughter cells. In contrast, during interphasethe cycling actin wave promotes localized mitochondrial fission. Here, we identify the F-actin nucleator/elongator FMNL1 as a positive regulator of the wave. Depletion of FMNL1 ablates the actin wave, allowing us to assess the functional consequences in interphase cells. FMNL1-depleted cells exhibit decreased mitochondrial polarization, decreased mitochondrial oxygen consumption, and increased production of reactive oxygen species. Accompanying these changes is a loss of hetero-fusion of wave-fragmented mitochondria. Thus we propose that the interphase actin wave maintains mitochondrial homeostasis by promoting mitochondrial content mixing. Finally, we investigated the mechanistic basis for the observation that the wave drives mitochondrial motility in metaphase but mitochondrial fission in interphase. Our data indicate that when the force of actin polymerization is resisted by mitochondrial tethering to microtubules, fission results. In striking contrast, upon microtubule depolymerization actin wave-enveloped mitochondria in interphase cells display comet tail motility characteristic of metaphase cells, which are devoid of microtubule-mitochondria interactions, suggesting that microtubule tethering inhibits comet tail-driven motility.
2024-06-23 | PXD050085 | Pride
Project description:Gastrointestinal health depends on the adaptive immune system tolerating the foreign proteins in food1,2. This tolerance is paradoxical because the immune system normally attacks foreign substances by generating inflammation. Here, we addressed this conundrum by using a sensitive cell enrichment method to assess how CD4+ helper T cells respond to peptides from food. Polyclonal CD4+ T cells responded to food peptides, including a natural one from gliadin, by proliferating weakly in secondary lymphoid organs of the gut-liver axis due to the action of regulatory T cells. A few food-specific T cells then differentiated into T follicular helper cells that promoted a weak antibody response. Most cells, however, lacked T helper lineage markers and became either naïve-like or T follicular helper-like anergic cells both with limited capacity to migrate to the lamina propria and form Th1 cells. Eventually, many of the T helper lineage-negative cells became Treg cells themselves via an IL-2-dependent mechanism. Our results indicate that food peptide-specific CD4+ T cells do not cause immunopathology because they are activated in a Treg cell-generated environment to become hyporesponsive cells that do not drive inflammation and are prone to become peripheral Treg cells.
2022-05-31 | GSE202423 | GEO