T cell-specific loss of Pten leads to defects in central and peripheral tolerance.
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.
Suzuki
A
A
Department of Molecular and Cellular Biology, Osaka University, 565-0871, Osaka, Japan.
Yamaguchi
M T
MT
Ohteki
T
T
Sasaki
T
T
Kaisho
T
T
Kimura
Y
Y
Yoshida
R
R
Wakeham
A
A
Higuchi
T
T
Fukumoto
M
M
Tsubata
T
T
Ohashi
P S
PS
Koyasu
S
S
Penninger
J M
JM
Nakano
T
T
Mak
T W
TW
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002455:Cell Division; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D004768:Enterotoxins / Q000276:immunology; D005260:Female; D016147:Genes, Tumor Suppressor; D020672:I-kappa B Proteins; D007108:Immune Tolerance; D008206:Lymphatic Diseases / Q000276:immunology; D016399:Lymphoma, T-Cell / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011946:Receptors, Antigen / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D013163:Splenomegaly; D013211:Staphylococcus aureus / Q000276:immunology; D018089:Superantigens / Q000276:immunology; D013950:Thymus Gland / Q000002:abnormalities / Q000166:cytology; D025521:Tumor Suppressor Proteins
D016207:Cytokines; D004268:DNA-Binding Proteins; D004768:Enterotoxins; C028507:H-Y antigen receptor; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011946:Receptors, Antigen; D011948:Receptors, Antigen, T-Cell; D018089:Superantigens; D025521:Tumor Suppressor Proteins; C031818:enterotoxin B, staphylococcal; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase