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Spatial microniches of IL-2 synergize with IL-10 to drive lung migratory Th2 cells in response to inhaled allergen [scRNA-Seq]

ABSTRACT: The mechanisms that guide Th2 cell differentiation in barrier tissues are unclear but important for the development of allergic asthma. Using temporal, spatial and single cell transcriptomic tracking of house dust mite (HDM) specific T cells, we describe the molecular pathways driving allergen-specific Th2 cells. Early Blimp-1 expression occurs in a subset of CD4 T cells in the lymph node prior to lung migration driven by IL-10 from allergen-specific T cells, but was not required for GATA3 upregulation. Instead, IL-2 via STAT5 was required to directly repress Bcl6 and Bach2 to support GATA3 and Blimp-1 upregulation. Loss of Blimp-1 during priming in the lymph node ablated the formation of Th2 cells that migrate to the lung, indicating early Blimp-1 promotes the population of Th2 cells with migratory capability. Spatial microniches of IL-2 in the lymph node discriminate and support these earliest Blimp-1+ migratory Th2 cells, demonstrating that lymph node localization is a primary driver of differentiation. Our findings illuminate the molecular pathways for inhaled allergens to promote Th2 cells and identify an early requirement for IL-2 mediated spatial microniches and allergen-driven IL-10 from responding T cells that drive allergic asthma.

ORGANISM(S): Mus musculus

PROVIDER: GSE245109 | GEO | 2024/02/26

REPOSITORIES: GEO

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Spatial microniches of IL-2 synergize with IL-10 to drive lung migratory Th2 cells in response to inhaled allergen [Curio]

Project description:The mechanisms that guide Th2 cell differentiation in barrier tissues are unclear but important for the development of allergic asthma. Using temporal, spatial and single cell transcriptomic tracking of house dust mite (HDM) specific T cells, we describe the molecular pathways driving allergen-specific Th2 cells. Early Blimp-1 expression occurs in a subset of CD4 T cells in the lymph node prior to lung migration driven by IL-10 from allergen-specific T cells, but was not required for GATA3 upregulation. Instead, IL-2 via STAT5 was required to directly repress Bcl6 and Bach2 to support GATA3 and Blimp-1 upregulation. Loss of Blimp-1 during priming in the lymph node ablated the formation of Th2 cells that migrate to the lung, indicating early Blimp-1 promotes the population of Th2 cells with migratory capability. Spatial microniches of IL-2 in the lymph node discriminate and support these earliest Blimp-1+ migratory Th2 cells, demonstrating that lymph node localization is a primary driver of differentiation. Our findings illuminate the molecular pathways for inhaled allergens to promote Th2 cells and identify an early requirement for IL-2 mediated spatial microniches and allergen-driven IL-10 from responding T cells that drive allergic asthma.

2024-02-20 | GSE245111 | GEO

Spatial microniches of IL-2 synergize with IL-10 to drive lung migratory Th2 cells in response to inhaled allergen [Spatial transcriptomics]

2024-02-20 | GSE245110 | GEO

Microarray analyses of lymph node dendritic cells (DCs) stimulated in vitro with papain or LPS

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IL-10 induces a STAT3-dependent autoregulatory loop in Th2 cells that promotes Blimp-1 restriction of cell expansion via antagonism of STAT5 target genes

Project description:Blimp-1 expression in T cells extinguishes the T follicular helper cell fate and drives terminal differentiation, but also limits autoimmunity. Although various factors have been described to control Blimp-1 expression in T cells, little is known about what regulates Blimp-1 expression in Th2 cells and the molecular basis of its actions. Herein, we report that STAT3 unexpectedly played a critical role in regulating Blimp-1 in Th2 cells. Furthermore, we found that the cytokine IL-10 acted directly on Th2 cells and was necessary and sufficient to induce optimal Blimp-1 expression through STAT3. Together, Blimp-1 and STAT3 amplified IL-10 production in Th2 cells, creating a strong autoregulatory loop that enhanced Blimp-1 expression. Increased Blimp-1 in T cells antagonized STAT5-regulated cell cycle and anti-apoptotic genes to limit cell expansion. These data elucidate the signals required for Blimp-1 expression in Th2 cells and reveal an unexpected mechanism of action of IL-10 in T cells, providing insights into the molecular underpinning by which Blimp-1 constrains T cell expansion to limit autoimmunity.

2018-02-06 | GSE110176 | GEO

The transcription factor GATA3 is critical for the development of all IL-7Ra-expressing innate lymphoid cells (ILCs) and maintenance of type 2 ILCs

Project description:Innate lymphoid cells (ILCs) play critical roles during innate immune responses to pathogens and lymphoid organ development. IL-7Ra+ ILC subsets, similar to T helper (Th) cell subsets, produce distinctive effector cytokines. The molecular control of IL-7Ra+ ILC development and maintenance has yet to be dissected. Here we report that GATA3 is indispensable for the development of all IL-7Ra+ ILC subsets and T cells. Gata3 conditional deficient mice have no lymph nodes and are susceptible to Citrobactor rodentium infection. Genome-wide gene analyses indicate that GATA3 regulates similar set of cytokines and receptors in ILC2s and Th2 cells and is critical for the maintenance of ILC2s. Thus, GATA3 plays parallel roles in establishing and regulating both adaptive and innate lymphocytes. To identify GATA3 regulated genes in type 2 innate lymphoid cells by tamoxifen-mediated acute deletion of Gata3 gene.

2014-03-13 | E-GEOD-47851 | biostudies-arrayexpress

Bcl11b- and GATA3-mediated gene regulation in Th2 cells

Project description:GATA-binding protein 3 (GATA3) acts as the master transcription factor for type 2 T helper (Th2) cell differentiation and function. However, it is still elusive how GATA3 function is precisely regulated in Th2 cells. Here, we report that the transcription factor B cell lymphoma 11b (Bcl11b), a previously unknown component of GATA3 transcriptional complex, is involved in GATA3-mediated gene regulation. Bcl11b binds to GATA3 through protein-protein interaction, and they co-localize at many important cis-regulatory elements in Th2 cells. The expression of type 2 cytokines, including IL-4, IL-5 and IL-13, is up-regulated in Bcl11b-deficient Th2 cells both in vitro and in vivo; such up-regulation is completely GATA3-dependent. Genome-wide analyses of Bcl11b- and GATA3-regulated gene (from RNA-Seq), co-binding pattern (from ChIP-Seq), and Bcl11b-mediated epigenetic changes (in H3K27ac and DHSs) suggest that GATA3/Bcl11b complex is involved in limiting Th2 gene expression, as well as in inhibiting non-Th2 gene expression. Thus, Bcl11b controls both GATA3-mediated gene activation and repression in Th2 cells.

2018-03-05 | GSE109107 | GEO

Bcl11b, a Novel GATA3-Interacting Protein, Suppresses Th1 while Limiting Th2 Cell Differentiation (H3K27ac and DNase-Seq)

2018-03-05 | GSE108633 | GEO

Microarray analyses of lymph node dendritic cells (DCs) stimulated in vitro with papain or LPS

Project description:T helper type 2 (Th2) responses are induced by protease allergens and helminthes. However the molecular mechanisms that initiate Th2 responses are poorly understood. To obtain insight into this mechanism, we performed a microarray analysis of lymph node DCs stimulated in vitro with the protease allergen papain, or with LPS, a Th1 inducing stimulus. Key words: Th2 response, LPS, dendritic cells, Papain CD11c+ DCs were isolated from the lymph nodes of C57BL/6 mice, and cultured in vitro (1x106 DCs per ml) with 500 3T3-CD40L fibroblasts, either alone, or in the presence of papain (25 µg/ml) or LPS (1 µg/ml). 4h and 17h later, the cells were harvested and RNA isolated and processed for microarray analyses. RNA was extracted and processed from freshly isolated LN DCs. For a given time point, the expression profile of DCs treated with papain or LPS, were compared to that of untreated DCs

2010-05-05 | E-GEOD-21602 | biostudies-arrayexpress

Determine MARCH1-dependent molecular differences in dendritic cells that carry allergen from the lungs to the draining lymph nodes

Project description:MARCH1-/- mice have a deficit in TH2 cell development in the mediastinal LN to HDM allergens. Pulmonary DCs that capture allergens and migrate to mediastinal lymph node have been implicated in driving TH2 cell polarization. We then investigated whether MARCH1 is involved in transcriptional reprograming of migratory DCs, which has been suggested to condition the DCs to drive TH2 cell development. To do this, we performed single cell RNA sequencing through the 10X Chromium platform of allergen-carrying WT or MARCH1-/- DCs in the LNs of mice.

2021-09-17 | GSE183861 | GEO

Neuroprotective protein ADNP-dependent histone remodeling complex promotes Th2 immune cell differentiation (RNA-Seq)

Project description:Type-2 immune responses are critical in tissue homeostasis, anti-helminth immunity and allergy. Th2 cells produce interleukin (IL)-4, IL-5 and IL-13 from the type-2 gene cluster under regulation by transcription factors (TFs) including GATA3. To better understand this system we performed CRISPR-Cas9 screens targeting 1131 TFs during Th2 cell differentiation. We discovered that ADNP is indispensable for immune reactions to allergen. Mechanistically, ADNP performs a previously unappreciated role in gene activation forming a critical bridge in the transition from pioneer TFs to chromatin remodelling by recruiting CHD4 and BRG1. Although GATA3 and AP-1 bound the type-2 cytokine locus in the absence of ADNP, they were unable to initiate histone acetylation or DNA accessibility, resulting in highly impaired type-2 cytokine expression. Similar ADNP-dependent regulation was observed for the Maf and Il4ra genes which are known regulators of Th2 differentiation. Our results demonstrate an important role for ADNP in promoting immune cell specialization.

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