MTOR coordinates transcriptional programs and mitochondrial metabolism of activated Treg subsets to protect tissue homeostasis
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ABSTRACT:
PROVIDER: PRJNA411780 | ENA |
REPOSITORIES: ENA
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Project description:Regulatory T (Treg) cells derived from the thymus (tTreg) and periphery (pTreg) play central and distinct roles in immunosuppression, but mechanisms governing the generation and activation of Treg subsets in vivo remain uncertain. Here, we report that mechanistic target of rapamycin (mTOR) unexpectedly supports the homeostasis and functional activation of tTreg and pTreg cells. Further, mTOR signaling is crucial for programming activated Treg cell effector function to protect immune tolerance and tissue homeostasis. Treg-specific deletion of mTOR drives spontaneous TH2 responses and altered barrier tissue homeostasis, associated with reductions in both thymic derived effector Treg (eTreg) and pTreg cells. Mechanistically, mTOR acts downstream of antigenic signals to drive IRF4 expression and mitochondrial metabolism, and accordingly, disruption of mitochondrial metabolism severely impairs Treg cell suppressive function and their homeostasis in tissues. Collectively, our results demonstrate that mTOR coordinates transcriptional and metabolic programs in activated Treg subsets to mediate tissue homeostasis
2019-09-12 | GSE104130 | GEO
Project description:Regulatory T (Treg) cells derived from the thymus (tTreg) and periphery (pTreg) have central and distinct functions in immunosuppression, but mechanisms for the generation and activation of Treg subsets in vivo are unclear. Here, we show that mechanistic target of rapamycin (mTOR) unexpectedly supports the homeostasis and functional activation of tTreg and pTreg cells. mTOR signaling is crucial for programming activated Treg-cell function to protect immune tolerance and tissue homeostasis. Treg-specific deletion of mTOR drives spontaneous effector T-cell activation and inflammation in barrier tissues and is associated with reduction in both thymic-derived effector Treg (eTreg) and pTreg cells. Mechanistically, mTOR functions downstream of antigenic signals to drive IRF4 expression and mitochondrial metabolism, and accordingly, deletion of mitochondrial transcription factor A (Tfam) severely impairs Treg-cell suppressive function and eTreg-cell generation. Collectively, our results show that mTOR coordinates transcriptional and metabolic programs in activated Treg subsets to mediate tissue homeostasis.
| S-EPMC5974344 | biostudies-literature
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:Roquin proteins are required to preclude spontaneous T cell activation and aberrant T follicular helper (Tfh) or T helper 17 (Th17) differentiation. Here, we show that deletion of Roquin encoding alleles in regulatory T cells (Tregs) also caused the activation of conventional T cells. These Tregs exhibited a follicular Treg phenotype, CD25 downregulation and could not protect from colitis. Mechanistically, Roquin was required for full expression and activity of Pten and Foxo1, two essential signaling molecules in Tregs and effector T cells. Roquin upregulated Pten by interfering with miR-17~92 binding to an overlapping cis-element in the Pten 3' UTR and downregulated the Foxo1-specific E3 ubiquitin ligase Itch. Loss of Roquin enhanced mTOR signaling and global protein synthesis, while inhibition of PI3K or mTOR in Roquin-deficient CD4+ T cells corrected increased Tfh and Th17 differentiation. Thereby, the control of PI3K-mTOR signaling by Roquin prevents autoimmunity through T cell-intrinsic and Treg-mediated regulation.
2018-01-08 | GSE86110 | GEO
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.
2012-08-07 | GSE36527 | GEO
Project description:The inflammasome initiates innate defense and inflammatory response by activating caspase-1 and pyroptotic cell death in myeloid cells1,2. It is comprised of an innate immune receptor/effector, pro-caspase-1 and a common adaptor molecule, ASC (apoptotic speck-containing protein with a CARD). Consistent with their pro-inflammatory function, inflammasome components including caspase-1, ASC and NLRP3, are known to exacerbate autoimmunity during experimental autoimmune encephalomyelitis (EAE) by enhancing IL-1 and IL-18 secretion in myeloid cells3-6. Here we show an unexpected function of a DNA-binding inflammasome effector, AIM2 (Absent in Melanoma 2)7-10, in restraining autoimmunity by performing EAE in both whole body and Treg-specific deletion of Aim2–/– mice. AIM2 is highly expressed by human and mouse Treg cells and it is essential to attenuate EAE. RNA-seq, biochemical and metabolic analyses revealed that AIM2 attenuates mTOR, Myc and immune-metabolic functions in both Treg cells isolated in vivo and Treg cells induced in vitro with TGF-. Importantly, we found AIM2 physically interacted with RACK1 in Treg cells to facility the PP2A/RACK1/Akt-mTOR signaling, which is identified as a central component downstream of AIM2 that controls Treg cell function and stability. While AIM2 is generally accepted as an inflammasome effector in myeloid cells, this report reveals a previously unappreciated T cell-intrinsic role of AIM2 in maintaining Treg cell function to restrain autoimmunity. This is achieved by diminishing Akt-mTOR signaling to regulate Treg stability under inflammation, and altering immune-metabolism in Treg cells.
2021-01-27 | PXD018638 | Pride
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
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. To identify genes and pathways enriched in CD49b+ Treg cells, we performed RNA-seq of splenic CD49b+ and CD49b− Treg cells that were of otherwise similar activation status based on expression of CD44 and CD62L. This revealed that splenic CD49b+ Treg cells express genes related to migration and activation, but are relatively depleted of genes whose expression is TCR-dependent in Treg cells. These results shed light on the identity and development of a functionally potent subset of mature effector Treg cells that recirculates through and surveys peripheral tissues.
2018-10-22 | GSE121482 | GEO
Project description:Regulatory T cells (Tregs) are immune cells that play a crucial role in maintaining tolerance to harmless antigens, including commensal microbes. In the intestine, Tregs can be classified into subsets based on their expression of transcription factors Helios, Rorg, Gata3 and cMaf. The exact functions of the intestinal Treg subsets and their role in maintaining tolerance to intestinal microbes is not fully understood. Here, we generated conditional knockout mice of each Treg subset and profiled the composition of their intestinal microbiota by performing 16S rRNA sequencing of stool from conditional knockouts and matched littermate controls.
2023-12-20 | GSE241887 | GEO
Project description:After activation, CD4+ T helper (Th) cells differentiate into functionally specialized populations that coordinate distinct immune responses and protect against different types of pathogens. In humans, these effector and memory Th cell subsets can be readily identified in peripheral blood based on their differential expression of chemokine receptors that govern their homeostatic and inflammatory trafficking. Foxp3+ regulatory T (Treg) cells can also be divided into subsets that phenotypically mirror each of these effector populations, and share expression of key transcription factors and effector cytokines. In this study, we performed comprehensive transcriptional profiling of 11 phenotypically distinct Th and Treg cell subsets sorted from peripheral blood of healthy individuals. Despite their shared phenotypes, we found that mirror Th and Treg subsets were transcriptionally dissimilar, and that Treg cell populations showed limited transcriptional diversity compared to Th cells. We identified core transcriptional signatures shared across all Th and Treg cell populations, and unique signatures that define each of the Th or Treg populations. Finally, we applied these signatures to bulk Th and Treg RNA-seq data and found enrichment of specific Th and Treg cell populations in different human tissues. These results further define the molecular basis for the functional specialization and differentiation of Th and Treg cell populations, and provide a new resource for examining Th and Treg specialization in RNA-seq data.
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