T Cell-Specific Loss of Pten Leads to Defects in Central and Peripheral Tolerance

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.