T cell-specific loss of Pten leads to defects in central and peripheral tolerance

Immunity. 2001 May;14(5):523-34. doi: 10.1016/s1074-7613(01)00134-0.

Abstract

PTEN, a tumor suppressor gene, is essential for embryogenesis. We used the Cre-loxP system to generate a T cell-specific deletion of the Pten gene (Pten(flox/-) mice). All Pten(flox/-) mice develop CD4+ T cell lymphomas by 17 weeks. Pten(flox/-) mice show increased thymic cellularity due in part to a defect in thymic negative selection. Pten(flox/-) mice exhibit elevated levels of B cells and CD4+ T cells in the periphery, spontaneous activation of CD4+ T cells, autoantibody production, and hypergammaglobulinemia. Pten(flox/-) T cells hyperproliferate, are autoreactive, secrete increased levels of Th1/Th2 cytokines, resist apoptosis, and show increased phosphorylation of PKB/Akt and ERK. Peripheral tolerance to SEB is also impaired in Pten(flox/-) mice. PTEN is thus an important regulator of T cell homeostasis and self-tolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / immunology
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Division
  • Cytokines / biosynthesis
  • DNA-Binding Proteins / metabolism
  • Enterotoxins / immunology
  • Female
  • Genes, Tumor Suppressor*
  • I-kappa B Proteins*
  • Immune Tolerance*
  • Lymphatic Diseases / immunology
  • Lymphoma, T-Cell / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinases / metabolism
  • PTEN Phosphohydrolase
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / immunology*
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Receptors, Antigen / genetics
  • Receptors, Antigen / immunology
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Splenomegaly
  • Staphylococcus aureus / immunology
  • Superantigens / immunology
  • Thymus Gland / abnormalities
  • Thymus Gland / cytology
  • Tumor Suppressor Proteins*

Substances

  • Cytokines
  • DNA-Binding Proteins
  • Enterotoxins
  • H-Y antigen receptor
  • I kappa B beta protein
  • I-kappa B Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Antigen
  • Receptors, Antigen, T-Cell
  • Superantigens
  • Tumor Suppressor Proteins
  • enterotoxin B, staphylococcal
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase