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Interferon dependent genes of intrathymic antigen presenting cells

ABSTRACT: The activation of thymic B cells is critical for their licensing as antigen presenting cells and resulting ability to mediate central tolerance. The processes leading to licensing are still not fully understood. By comparing thymic B cells to activated Peyer’s Patch B cells at steady state, we found that thymic B cell activation starts during the neonatal period and is characterized by TCR/CD40 dependent activation, followed by immunoglobulin class switch recombination (CSR) without forming germinal centers. Transcriptional analysis also demonstrated a strong interferon signature, which was not apparent in the periphery. Thymic B cell activation and CSR were primarily dependent on type III IFN signaling, and loss of type III IFN receptor in thymic B cells resulted in reduced thymocyte regulatory T cell (Treg) development. Finally, from TCR deep sequencing, we estimate that licensed B cells induce development of a substantial fraction of the Treg cell repertoire. Together, these findings reveal the importance of steady state type III IFN in generating licensed thymic B cells that generate T cell tolerance to activated B cells

ORGANISM(S): Mus musculus

PROVIDER: GSE192716 | GEO | 2023/03/15

REPOSITORIES: GEO

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Type III interferon drives thymic B cell activation and regulatory T cell generation

Project description:The activation of thymic B cells is critical for their licensing as antigen presenting cells and resulting ability to mediate central tolerance. The processes leading to licensing are still not fully understood. By comparing thymic B cells to activated Peyer’s Patch B cells at steady state, we found that thymic B cell activation starts during the neonatal period and is characterized by TCR/CD40 dependent activation, followed by immunoglobulin class switch recombination (CSR) without forming germinal centers. Transcriptional analysis also demonstrated a strong interferon signature, which was not apparent in the periphery. Thymic B cell activation and CSR were primarily dependent on type III IFN signaling, and loss of type III IFN receptor in thymic B cells resulted in reduced thymocyte regulatory T cell (Treg) development. Finally, from TCR deep sequencing, we estimate that licensed B cells induce development of a substantial fraction of the Treg cell repertoire. Together, these findings reveal the importance of steady state type III IFN in generating licensed thymic B cells that induce T cell tolerance to activated B cells.

2023-02-13 | GSE220104 | GEO

TGF-β1 licensed murine mesenchymal stromal cells show superior therapeutic efficacy in modulating corneal allograft immune rejection in vivo

Project description:We report a novel licensing strategy to improve the immunosuppressive capacity of MSCs. Licensing murine MSCs with TGF-β1 (TGF-β MSC) significantly improved their ability to modulate both the phenotype and secretome of inflammatory bone marrow-derived macrophages and significantly increased the numbers of regulatory T lymphocytes (Tregs) following co-culture assays. These TGF-β MSC-expanded Tregs also expressed significantly higher levels of PD-L1 and CD73, indicating enhanced suppressive potential. Detailed analysis of T lymphocyte co-cultures revealed modulation of secreted factors, most notably, elevated prostaglandin E2 (PGE2). Furthermore, TGF-β MSCs could significantly prolong rejection-free survival (69.2% acceptance rate compared to 21.4% for un-licensed MSC treated recipients) in a murine corneal allograft model. Mechanistic studies revealed that (i) therapeutic efficacy of TGF-β MSCs is Smad2/3-dependent; (ii) TGF-β MSC’s enhanced immunosuppressive capacity is contact-dependent and (iii) enhanced secretion of PGE2 (via prostaglandin EP4 receptor) by TGF-β MSCs is the predominant mediator of Treg expansion and T cell activation and is associated with corneal allograft survival. Collectively, we provide compelling evidence for the use of TGF-β1 licensing as an unconventional strategy for enhancing MSC immunosuppressive capacity.

2020-08-31 | GSE150008 | GEO

Licensing Delineates Helper and Effector NK Cell Subsets During Viral Infection

Project description:Natural killer (NK) cells can be divided into phenotypic subsets based on the expression of receptors that bind self-MHC-I molecules with differing affinities; a concept termed licensing or education. Here we show that NK cell subsets exhibit markedly different migratory, effector, and immunoregulatory functions on dendritic cells and antigen-specific CD8+ T cell responses during influenza and murine cytomegalovirus infections. Shortly after infection, unlicensed NK cells preferentially trafficked to draining lymph nodes and produced GM-CSF, which promoted the expansion and activation of dendritic cells, and ultimately resulted in sustained antigen-specific CD8+ T cell responses. In contrast, licensed NK cells preferentially migrated to infected parenchymal tissues and produced greater levels of interferon-γ (IFN-γ). Importantly, human NK cell subsets exhibited similar phenotypic characteristics and patterns of cytokine production. Collectively, our studies demonstrate a critical demarcation between the functions of licensed and unlicensed NK cell subsets, with the former functioning as the classical effector subset in inflamed tissues and the latter as modulators of adaptive immunity helping to prime immune responses in draining lymph nodes.

2017-08-22 | GSE72632 | GEO

APCEDENÂ , Dendritic cell based Immunotherapy for the treatment of cancer.

Project description:Primary outcome(s): 1. Overall Survival 2. Evaluation of objective response through Immune related Response Criteria (irRC): measure of PD; PR and SD. 3. Immune response as assessed through Treg population and serum IFN-Î³ levels 4. Monitor treatment emergent adverse events. Timepoint: 1. Overall Survival 2. Evaluation of objective response through Immune related Response Criteria (irRC): measure of PD; PR and SD. 3. Immune response as assessed through Treg population and serum IFN-Î³ levels 4. Monitor treatment emergent adverse events.

| 2581299 | ecrin-mdr-crc

DRAK2 alters IL-2 sensitivity and Treg development

Project description:Drak2¬-deficient (Drak2-/-) mice are resistant to multiple models of autoimmunity, yet effectively eliminate pathogens and tumors. Thus, DRAK2 is an ideal target to treat autoimmune diseases. However, the mechanisms by which DRAK2 contributes to autoimmunity, particularly type 1 diabetes (T1D), remain unresolved. Our data indicate that DRAK2 contributes to autoimmunity in multiple ways by regulating thymic Treg development and by impacting the sensitivity of conventional T cells to Treg-mediated suppression.

2023-02-09 | PXD037922 | Pride

RELA tunes innate-like interferon I/III responses in human T cells

Project description:In innate immune cells, intracellular sensors such as cGAS-STING stimulate type I/III interferon (IFN) expression, which promotes antiviral defense and immune activation. However, how IFN-I/III expression is controlled in adaptive cells is poorly understood. Here, we identify a transcriptional rheostat orchestrated by RELA that confers human T cells with innate-like abilities to produce IFN-I/III. Despite intact cGAS-STING signaling, IFN-I/III responses are stunted in CD4+ T cells compared with dendritic cells or macrophages. We find that lysine residues in RELA tune the IFN-I/III response at baseline and in response to STING stimulation in CD4+ T cells. This response requires positive feedback driven by cGAS and IRF7 expression. By combining RELA with IRF3 and DNA demethylation, IFN-I/III production in CD4+ T cells reaches levels observed in dendritic cells. IFN-I/III production provides self-protection of CD4+ T cells against HIV infection and enhances the elimination of tumor cells by CAR T cells. Therefore, innate-like functions can be tuned and leveraged in human T cells.

2023-02-16 | GSE182647 | GEO

Single-cell RNA-seq of murine thymic Treg cell progenitors and mature Treg cells

Project description:We use single-cell RNA-seq to determine distinct selection phenotypes of 2 rare thymic Treg cell progenitors as well as mature thymic Treg cells

2018-12-31 | GSE123067 | GEO

Gene expression analysis of OX40-triggered mouse Treg

Project description:Regulatory T (Treg) maintain the tumor microenvironment in an immunosuppressive state preventing effective anti-tumor immune response. A possible strategy to overcome Treg cell suppression focuses on OX40, a costimulatory molecule expressed constitutively by Treg cells while induced in activated effector T (Teff) cells. OX40 stimulation by the agonist mAb OX86 inhibits Treg cell suppression and boosts Teff cell activation. Here we uncover the mechanisms underlying the therapeutic activity of OX86 treatment dissecting its distinct effects on Treg and on effector memory T (Tem) cells, which are the most abundant CD4+ populations strongly expressing OX40 at the tumor site. In response to OX86, tumor-infiltrating Treg cells produced significantly less interleukin 10 (IL-10), possibly in relation to a decrease in the transcription factor IRF1. Tem cells responded to OX86 by upregulating surface CD40L expression, providing a licensing signal to dendritic cells (DCs). The CD40L/CD40 axis was required for Tem cell-mediated in vitro DC maturation and in vivo DC migration. Accordingly, OX86 treatment was no longer therapeutic in CD40 KO mice. In conclusion, following OX40 stimulation, blockade of Treg cell suppression and enhancement of the Tem cell adjuvant effect both concurred to free DCs from immunosuppression and to activate the immune response against the tumor. Total RNA obtained from sorted mouse FoxP3-GFP+ Treg activated in vitro with anti-CD3 in the presence of an OX40-agonist mAb (OX86) or isotype control.

2011-09-25 | E-GEOD-32373 | biostudies-arrayexpress

Interferon-λ enhances the differentiation of naïve B-cells into plasmablasts via mTORC1 pathway

Project description:Type III interferon (IFN-λ) is known to be a potential immune modulator, but the mechanisms behind its immune-modulatory functions and its impact on plasmablast differentiation in humans, remain unknown. Human B-cells and their subtypes directly respond to IFN-λ. We performed B-cell transcriptome profiling to investigate the immune-modulatory role of IFN-λ in B-cells. We found that IFN-λ induced gene expression in B cells is steady, prolonged and importantly cell type-specific. Further, IFN-λ enhances the mTORC1 (mammalian/mechanistic target 34 of rapamycin complex 1) pathway in the B-cell receptor-activated B-cells (BCR/anti-IgM). The engagement of mTORC1 by BCR and IFN-lambda induces the cell cycle progress in B-cells. Subsequently, IFN-λ boosts the differentiation of naïve B-cells into plasmablast upon activation and the cells gain effector functions such as cytokine release (IL-6, IL-10) and antibody production. Our study shows how IFN-λ systematically boosts the differentiation of naïve B-cells into plasmablasts by enhancing the mTORC1 pathway and cell cycle progression in activated B-cells, which is a previously unknown immune modulatory role of IFN-λ.

2020-08-14 | GSE156195 | GEO

Oleic Acid Availability Preprograms Early Thymocytes for Treg Cell Commitment in the Periphery [Rna-seq]

Project description:The natures of activation signals are essential in determining T cell subset differentiation, however, the properties of T cell subset preference acquired during intrathymic development remain elusive. Here we show that naïve CD4+ T cells generated in the thymic microenvironment lacking SCD1, the enzyme catalyzing oleic acid production, exhibit enhanced Treg cell differentiation and confer on mice the ability to resist EAE. SCD1 deletion in K14+ thymic epithelia recapitulated the enhanced Treg cell differentiation phenotype of SCD1 knockout mice. The dearth of oleic acid permitted Dot1L to increase H3K79me2 level at the Atp2a2 locus of thymocytes at the DN2-DN3 transition stage. Such epigenetic modification persisted to naïve CD4+ T cells and facilitated Atp2a2 expression. Upon TCR activation, Atp2a2 enhanced the activity of calcium-NFAT1-Foxp3 axis to promote naïve CD4+ T cells to differentiate into Treg cells. Therefore, oleic acid availability is critical for preprogramming thymocytes with Treg differentiation propensities in periphery.

2023-09-30 | GSE237819 | GEO

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