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In Vitro Differentiation of Naive CD4+ T Cells into Pathogenic Th17 Cells in Mouse
Published on: October 25, 2024
Notch signaling regulates mouse and human Th17 differentiation
Shilpa Keerthivasan1, Reem Suleiman, Rebecca Lawlor
1Molecular Biology Program, Loyola University Medical Center, Maywood, IL 60153, USA.
Journal of Immunology (Baltimore, Md. : 1950)
|June 21, 2011
Summary
Notch signaling is crucial for the development of Th17 cells, which are involved in immunity and autoimmune diseases. Inhibiting Notch signaling reduces Th17 cell activity and disease progression in models of multiple sclerosis.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- T helper 17 (Th17) cells are vital for combating extracellular pathogens but also contribute to autoimmune and inflammatory diseases.
- Understanding the regulation of Th17 cell differentiation is essential for developing therapeutic strategies.
- Notch signaling plays a known role in T cell development and differentiation.
Purpose of the Study:
- To investigate the role of Notch signaling in Th17 cell differentiation.
- To identify the direct transcriptional targets of Notch signaling in Th17 cells.
- To evaluate the therapeutic potential of Notch inhibition in autoimmune disease models.
Main Methods:
- Activation of Notch1 in mouse and human in vitro-polarized Th17 cells.
- Blockade of Notch signaling to assess its impact on Th17 cytokine production.
- Promoter reporter assays, knockdown studies, and chromatin immunoprecipitation to identify direct transcriptional targets.
- In vivo inhibition of Notch signaling in a mouse model of multiple sclerosis (experimental autoimmune encephalomyelitis).
Main Results:
- Notch1 is activated in polarized Th17 cells from both mice and humans.
- Notch signaling blockade significantly reduced Th17-associated cytokine production.
- Interleukin-17 (IL-17) and retinoic acid-related orphan receptor gamma t (RORγt) were identified as direct transcriptional targets of Notch signaling.
- Inhibition of Notch signaling in vivo decreased IL-17 production and ameliorated disease progression in experimental autoimmune encephalomyelitis.
Conclusions:
- Notch signaling is intrinsically required for Th17 cell differentiation in both mice and humans.
- Notch signaling directly regulates the expression of key Th17-associated genes, including IL-17 and RORγt.
- Targeted inhibition of Notch signaling presents a potential therapeutic strategy for autoimmune disorders like multiple sclerosis.
Related Concept Videos
03:14Notch Signaling Pathway
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 until 1985...
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 until 1985...
03:14Notch Signaling Pathway
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 until 1985...
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 until 1985...
01:12Role Of Notch Signalling In Intestinal Stem Cell Renewal
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...
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...
02:33Hedgehog Signaling Pathway
The Hedgehog gene (Hh) was first discovered due to its control of the growth of disorganized, hair-like bristles phenotype in Drosophila, much like hedgehog spines. Hh plays a crucial role in the development of organs and the maintenance of homeostasis in both invertebrates and vertebrates. However, while Drosophila has only one Hh protein, mammals have multiple functional Hedgehog proteins - Sonic (Shh), Desert (Dhh), and Indian Hedgehog (Ihh). All of these homologous proteins have adapted to...
01:24T Cell Types and Functions
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...
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...