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Impaired Fas response and autoimmunity in Pten+/- mice

A Di Cristofano1, P Kotsi, Y F Peng

  • 1Department of Human Genetics-Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, 1275 York Avenue, New York, NY 10021, USA.

Science (New York, N.Y.)
|September 25, 1999
PubMed

Insights

Mutations in the PTEN gene cause autoimmune disorders by impairing Fas-mediated apoptosis. Inhibiting phosphatidylinositol 3-kinase (PI3K) restored Fas function, implicating the PI3K/Akt pathway in this process.

Area of Science:

  • Immunology
  • Genetics
  • Molecular Biology

Background:

  • Inactivating mutations in the PTEN tumor suppressor gene are linked to human disorders with tumor susceptibility.
  • PTEN encodes a phosphatase crucial for cellular regulation.
  • Autosomal dominant disorders associated with PTEN mutations are not fully understood.

Purpose of the Study:

  • To investigate the role of PTEN in autoimmune disorders.
  • To elucidate the mechanism by which PTEN mutations affect immune cell function.
  • To explore the connection between PTEN, Fas-mediated apoptosis, and autoimmunity.

Main Methods:

  • Generation and analysis of Pten heterozygous (Pten+/-) mice.
  • Assessment of autoimmune disorder development in Pten+/- mutants.
  • Evaluation of Fas-mediated apoptosis and T lymphocyte responses.
  • Treatment of Pten+/- cells with phosphatidylinositol (PI) 3-kinase inhibitors.

Main Results:

  • Pten+/- mice developed a lethal polyclonal autoimmune disorder.
  • Fas-mediated apoptosis was impaired in Pten+/- mice.
  • T lymphocytes from Pten+/- mice exhibited reduced activation-induced cell death and increased proliferation.
  • Phosphatidylinositol (PI) 3-kinase inhibitors restored Fas responsiveness in Pten+/- cells.

Conclusions:

  • PTEN is essential for mediating the Fas response and suppressing autoimmunity.
  • The PI 3-kinase/Akt pathway is implicated in PTEN's role in Fas-mediated apoptosis.
  • PTEN deficiency contributes to autoimmune pathogenesis through dysregulation of immune cell apoptosis and proliferation.

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