Single cell RNA sequecing of Gene epxressions and TCR clones in late-onset EAE
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE182747 | GEO | 2024/08/25
REPOSITORIES: GEO
Similar Datasets
Project description:Disease activity of autoimmune disorders such as multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) is temporarily suppressed by pregnancy. However, whether disease amelioration is due to non-specific immunomodulation or mediated by antigen-specific regulation of disease-causing conventional T cells (Tcon) and immuno- suppressive regulatory T cells (Treg), remains elusive. In the present study, we systematically analyzed changes of the T cell receptor (TCR) β repertoire driven by EAE and pregnancy using TCR sequencing. We demonstrate that EAE, but not pregnancy, robustly increased TCR repertoire clonality in both peripheral Tcon and Treg. Notably, pregnancy was required for the expansion of Treg harboring the dominant EAE-associated TRBV chain 13.2 and increased the frequency of EAE-associated clonotypes within the Treg compartment. Our findings indicate that pregnancy supports the expansion of Treg clonotypes that are equipped to recognize EAE- associated antigens. These Treg are thereby particularly suited to control corresponding encephalitogenic Tcon responses and likely contribute to pregnancy-associated protection in autoimmunity.
2019-07-30 | GSE122894 | GEO
Project description:single cell RNA sequecing of Gene epxressions and TCR clones in late-onset EAE
| PRJNA757703 | ENA
Project description:Understanding human regulatory T cells (Tregs) heterogeneity may identify markers of disease pathogenesis and facilitate the development of optimized cellular therapeutics. To better elucidate human Treg subsets, we conducted direct transcriptional profiling of CD4+FOXP3+Helios+ thymic-derived Treg (tTreg) and CD4+FOXP3+Helios- peripherally-induced Treg (pTreg), followed by comparison to CD4+FOXP3-Helios- T conventional (Tconv) cells. This analysis revealed that the coinhibitory receptor T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) was highly expressed on tTreg. In this study CD4 T cells were stained for the Treg-associated transcription factors FOXP3 and Helios, and subsequently FACS sorted to yield three populations: tTreg (CD4+FOXP3+Helios+), pTreg (CD4+FOXP3+Helios–) and the reference population Tconv (CD4+FOXP3–Helios–). A direct transcriptional profile was obtained from the recovered RNA from the populations defined as tTreg, pTreg, and Tconv.
2015-04-30 | E-GEOD-61834 | biostudies-arrayexpress
Project description:Genome-wide association studies identifying hundreds of susceptibility loci for autoimmune diseases indicate that genes active in immune cells predominantly mediate risk. Identification and functional characterization of causal variants remains challenging. Here, we focused on the immunomodulatory role of a protective variant in HDAC7 (rs148755202, HDAC7.p.R166H), identified in a study of low-frequency coding variation in multiple sclerosis (MS). Through transcriptomic analysis, we demonstrate that HDAC7 regulates genes essential for the function of FoxP3+ regulatory T cells (Tregs), an immunosuppressive subset of CD4 T cells that is dysfunctional in patients with MS. Moreover, Treg cell-specific conditional hemizygous deletion of HDAC7 increases severity of experimental autoimmune encephalitis (EAE), a mouse model of MS. Strikingly, Tregs transduced with the protective HDAC7 R166H variant exhibit higher suppressive capacity in an in vitro functional assay, mirroring functional defects previously observed in patients. In vivo modelling of the human HDAC7 R166H variant, by generation of a knock-in mouse model bearing the orthologous R150H substitution, showed decreased EAE severity linked to transcriptomic alterations of brain infiltrating Tregs as assessed by single cell RNA-seq. Our data suggest that dysregulation of epigenetic modifiers, a novel molecular class associated with disease risk, can influence disease onset. Finally, our approach provides a template for translation of genetic susceptibility loci to detailed functional characterization, using human in vitro and mouse in vivo modelling.
2022-10-17 | GSE215819 | GEO
Project description:Genome-wide association studies identifying hundreds of susceptibility loci for autoimmune diseases indicate that genes active in immune cells predominantly mediate risk. Identification and functional characterization of causal variants remains challenging. Here, we focused on the immunomodulatory role of a protective variant in HDAC7 (rs148755202, HDAC7.p.R166H), identified in a study of low-frequency coding variation in multiple sclerosis (MS). Through transcriptomic analysis, we demonstrate that HDAC7 regulates genes essential for the function of FoxP3+ regulatory T cells (Tregs), an immunosuppressive subset of CD4 T cells that is dysfunctional in patients with MS. Moreover, Treg cell-specific conditional hemizygous deletion of HDAC7 increases severity of experimental autoimmune encephalitis (EAE), a mouse model of MS. Strikingly, Tregs transduced with the protective HDAC7 R166H variant exhibit higher suppressive capacity in an in vitro functional assay, mirroring functional defects previously observed in patients. In vivo modelling of the human HDAC7 R166H variant, by generation of a knock-in mouse model bearing the orthologous R150H substitution, showed decreased EAE severity linked to transcriptomic alterations of brain infiltrating Tregs as assessed by single cell RNA-seq. Our data suggest that dysregulation of epigenetic modifiers, a novel molecular class associated with disease risk, can influence disease onset. Finally, our approach provides a template for translation of genetic susceptibility loci to detailed functional characterization, using human in vitro and mouse in vivo modelling.
2022-10-17 | GSE215818 | GEO
Project description:Genome-wide association studies identifying hundreds of susceptibility loci for autoimmune diseases indicate that genes active in immune cells predominantly mediate risk. Identification and functional characterization of causal variants remains challenging. Here, we focused on the immunomodulatory role of a protective variant in HDAC7 (rs148755202, HDAC7.p.R166H), identified in a study of low-frequency coding variation in multiple sclerosis (MS). Through transcriptomic analysis, we demonstrate that HDAC7 regulates genes essential for the function of FoxP3+ regulatory T cells (Tregs), an immunosuppressive subset of CD4 T cells that is dysfunctional in patients with MS. Moreover, Treg cell-specific conditional hemizygous deletion of HDAC7 increases severity of experimental autoimmune encephalitis (EAE), a mouse model of MS. Strikingly, Tregs transduced with the protective HDAC7 R166H variant exhibit higher suppressive capacity in an in vitro functional assay, mirroring functional defects previously observed in patients. In vivo modelling of the human HDAC7 R166H variant, by generation of a knock-in mouse model bearing the orthologous R150H substitution, showed decreased EAE severity linked to transcriptomic alterations of brain infiltrating Tregs as assessed by single cell RNA-seq. Our data suggest that dysregulation of epigenetic modifiers, a novel molecular class associated with disease risk, can influence disease onset. Finally, our approach provides a template for translation of genetic susceptibility loci to detailed functional characterization, using human in vitro and mouse in vivo modelling.
2022-10-17 | GSE215817 | 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: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 expressing the transcription factor Foxp3 are an essential suppressive CD4 T cell lineage of dual origin: Foxp3 induction in thymocytes and mature CD4 T cells gives rise to thymic (tTreg) and peripheral (pTreg) Treg cells, respectively. While tTreg cells primarily suppress autoimmunity, pTreg cells are thought to enforce tolerance to food and commensal microbiota. However, the role of Foxp3 in pTreg cells and the mechanisms underlying their differentiation and function remain poorly understood. Here, we used genetic lineage tracing to unambiguously identify microbiota-induced pTreg cells and found that many of their distinct features were Foxp3-independent. Lineage-committed, microbiota-dependent pTreg-like cells persisted in the colon in the absence of Foxp3 protein. While Foxp3 was critical for the suppression of a Th17 cell program, colitis and rampant mastocytosis, pTreg cells suppressed colonic effector T cell expansion in a Foxp3-independent manner. Thus, Foxp3 and the tolerogenic signals that precede and promote its expression independently confer distinct facets of pTreg functionality.
2022-06-17 | GSE193780 | 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