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Related Concept Videos

Notch Signaling Pathway03:14

Notch Signaling Pathway

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The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not...
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Role Of Notch Signalling In Intestinal Stem Cell Renewal01:12

Role Of Notch Signalling In Intestinal Stem Cell Renewal

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Notch signaling was first discovered in Drosophila melanogaster, where it is involved in cell lineage differentiation. Notch signaling regulates the maintenance and differentiation of intestinal stem cells or ISCs by controlling the expression of atonal homolog 1 or Atoh1. Atoh1 directs cells to differentiate into secretory cells.
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
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T Cell Activation and Clonal Selection01:22

T Cell Activation and Clonal Selection

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T cells are integral to our adaptive immune system, recognizing and effectively responding to foreign antigens. T cell activation and clonal selection are pivotal in orchestrating this immune response. This article elucidates these mechanisms, detailing the roles of cluster of differentiation (CD) markers, major histocompatibility complex (MHC) molecules, costimulatory signals, and the process of clonal selection.
Naive T cells that have not yet encountered an antigen express two primary CD...
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T Cell Types and Functions01:24

T Cell Types and Functions

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When T cells with CD4 markers are activated, they give rise to two types of effector cells: helper T cells and regulatory T cells. Meanwhile, T cells with CD8 markers differentiate into effector cytotoxic T cells. The differentiation of CD4 T cells into helper T cell subsets, such as Th1, Th2, and Th17 cells, is dependent on the antigen type, antigen-presenting cell, and regulatory cytokines.
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
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TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

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The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
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Introduction to Fibroblasts01:09

Introduction to Fibroblasts

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Rudolph Virchow discovered spindle-shaped cells called fibroblasts in 1858. Inactive fibroblasts, called fibrocytes, become activated by various stimuli, such as growth factors and inflammatory cytokines. Activated fibroblasts play a crucial role in wound healing, inflammation, formation of new blood vessels, and cancer progression. Uncontrolled activation of fibroblasts results in fibrosis, the excess deposition of fibrous tissue, which can lead to scarring and affect normal organs. This...
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Isolation of Papillary and Reticular Fibroblasts from Human Skin by Fluorescence-activated Cell Sorting
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Early Notch signals from fibroblastic reticular cells program effector CD8+ T cell differentiation.

Dave Maurice De Sousa1,2,3, Eric Perkey4, Laure Le Corre1,2,3

  • 1Maisonneuve-Rosemont Hospital Research Center, University of Montreal , Montreal, Canada.

The Journal of Experimental Medicine
|March 20, 2025
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Notch signaling, driven by fibroblastic reticular cells, promotes effector CD8+ T cell generation. This process involves specific molecular signatures and chromatin changes crucial for immune responses to infection and cancer.

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Area of Science:

  • Immunology
  • Cellular Biology
  • Molecular Biology

Background:

  • Understanding CD8+ T cell differentiation is key for developing therapies against infections and cancer.
  • Notch signaling is implicated in immune cell development, but its specific role in CD8+ T cell differentiation requires further elucidation.

Purpose of the Study:

  • To investigate the cellular and molecular mechanisms by which Notch signaling regulates the generation of effector CD8+ T cells.
  • To identify the primary source of Notch signals and the downstream molecular events driving CD8+ T cell differentiation during immune responses.

Main Methods:

  • Utilized genetic mouse models and blocking antibodies to study Notch signaling pathways.
  • Conducted transcriptional and epigenetic analyses to identify Notch-driven gene expression and chromatin modifications.
  • Investigated the role of fibroblastic reticular cells and Delta-like ligands in T cell activation.

Main Results:

  • Fibroblastic reticular cells, not dendritic cells, are the main source of Notch signals for T cells during early immune responses.
  • Identified a unique Notch-driven transcriptional and epigenetic signature in CD8+ T cells.
  • Early Notch signaling promotes chromatin opening at BATF-binding sites, crucial for CD8+ T cell differentiation.

Conclusions:

  • Fibroblastic reticular cells in lymphoid organ niches deliver critical early Notch signals that dictate CD8+ T cell differentiation.
  • These signals establish a molecular program essential for effective immune responses against infections and cancer.