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Related Experiment Videos

Lymphotoxin pathway directs thymic Aire expression.

Robert K Chin1, James C Lo, Oliver Kim

  • 1Department of Pathology and Committee in Immunology, The University of Chicago, Chicago, Illinois 60637, USA.

Nature Immunology
|October 1, 2003
PubMed
Summary
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Lymphotoxin signaling is essential for the autoimmune regulator Aire expression, crucial for central tolerance. Its absence causes autoimmunity, while its stimulation enhances Aire and self-antigen presentation in the thymus.

Area of Science:

  • Immunology
  • Molecular Biology
  • Autoimmunity

Background:

  • The autoimmune regulator Aire is critical for central tolerance, preventing autoimmune diseases.
  • Aire deficiency in humans leads to autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
  • The regulatory signals controlling Aire expression remain largely unknown.

Purpose of the Study:

  • To investigate the cellular signals regulating Aire expression.
  • To determine the role of lymphotoxin signaling in Aire-mediated central tolerance.

Main Methods:

  • Analysis of Aire expression in lymphotoxin-deficient and lymphotoxin-beta receptor-deficient mice.
  • Stimulation of lymphotoxin-beta receptor using agonistic antibodies.
  • Assessment of Aire and tissue-restricted antigen expression in thymic tissues and cell lines.

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Main Results:

  • Lymphotoxin signaling is necessary for Aire expression and its target genes.
  • Aire induction failure in lymphotoxin-deficient mice leads to autoimmunity.
  • Lymphotoxin-beta receptor stimulation increases Aire and tissue-restricted antigen expression.

Conclusions:

  • Lymphotoxin signaling is a key regulator of Aire expression.
  • This pathway is vital for establishing central tolerance by controlling Aire-dependent self-antigen presentation.
  • Defines essential thymocyte-stroma cross-talk for immune homeostasis.