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Related Concept Videos

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.
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T Cell Activation and Clonal Selection01:22

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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.
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Special Features of Adaptive Immunity01:20

Special Features of Adaptive Immunity

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The adaptive immune system, a crucial component of the overall immune response, offers a highly specialized defense against pathogens. It involves specific cell types and features, enabling it to combat infections effectively and efficiently.
The primary cell types involved in adaptive immunity are T cells and B cells. Each type has a unique role in defending the body against pathogens. T cells are responsible for cell-mediated immunity. They identify and eliminate infected cells directly,...
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Cell-mediated Immune Responses01:40

Cell-mediated Immune Responses

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Overview
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Inflammatory Response01:28

Inflammatory Response

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An inflammatory response is a localized, nonspecific immune reaction that occurs when a tissue is injured. It is characterized by redness, swelling, heat, and pain, which are commonly called the cardinal signs and symptoms of inflammation. Inflammation can sometimes result in a loss of function.
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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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Related Experiment Video

Updated: Aug 16, 2025

Adenoviral Transduction of Naive CD4 T Cells to Study Treg Differentiation
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Adenoviral Transduction of Naive CD4 T Cells to Study Treg Differentiation

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How GRAIL controls Treg function to maintain self-tolerance.

C Garrison Fathman1, Linda Yip1, Diana Gómez-Martín2

  • 1Department of Medicine, School of Medicine, Stanford University, Palo Alto, CA, United States.

Frontiers in Immunology
|December 26, 2022
PubMed
Summary
This summary is machine-generated.

Restoring regulatory T cell (Treg) function, not number, is key for treating autoimmunity. A targeted drug conjugate (PDC) effectively restored Treg function and prevented autoimmune diseases in mice.

Keywords:
GRAILcullin RING ligaseimmune regulationlow dose IL-2neddylationprotein drug conjugatesregulatory T cell

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Area of Science:

  • Immunology
  • Autoimmunity
  • Drug Development

Background:

  • Regulatory T cells (Tregs) maintain self-tolerance but are dysfunctional in autoimmune diseases.
  • Current therapies for autoimmunity are often ineffective and toxic.
  • Low-dose IL-2 therapy increases Treg numbers but not function.

Purpose of the Study:

  • To investigate the mechanism of Treg dysfunction in autoimmunity.
  • To develop a targeted therapy to restore Treg function and stability.

Main Methods:

  • Investigated the role of GRAIL (a ubiquitin E3 ligase) in Treg function.
  • Identified cullin5 as a GRAIL target protein involved in IL-2 receptor (IL-2R) signaling.
  • Developed a protein drug conjugate (PDC) delivering a neddylation activating enzyme inhibitor (NAEi) to Tregs via IL-2.

Main Results:

  • GRAIL deficiency impairs Treg function by promoting IL-2R desensitization and mTOR activation.
  • GRAIL ubiquitinates cullin5, inhibiting its neddylation and subsequent cullin ring ligase activity.
  • The PDC effectively restored Treg function and prevented autoimmune diseases (type 1 diabetes, lupus, MS) and allergic asthma in mouse models without toxicity.

Conclusions:

  • Defects in GRAIL-mediated regulation of IL-2R signaling contribute to Treg dysfunction in autoimmunity.
  • Targeted delivery of NAEi using a PDC can restore Treg function and treat autoimmune and allergic diseases.
  • This PDC strategy offers a novel, safe, and effective approach to autoimmune disease therapy.