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-IoxP system to generate a T cell-specific deletion of the Pten gene (Pten(floxl-) mice). All Pten(floxl-) mice develop CD4(+) T cell lymphomas by 17 weeks. Pten(floxl-) mice show increased thymic cellularity due in part to a defect in thymic negative selection. Pten(floxl-) 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(floxl-) 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 SEE is also impaired in Pten(floxl-) mice. PTEN is thus an important regulator of T cell homeostasis and self-tolerance.