Conditional Deletion of PTEN in Peripheral T Cells Augments TCR-Mediated Activation but Does Not Abrogate CD28 Dependency or Prevent Anergy Induction

PTEN is thought to play a critical role in T cell activation by negatively regulating the PI3K signaling pathway important for cellular activation, growth, and proliferation. To directly eliminate PTEN in postthymic T cells for studies of functional effects, we used CAR transgenic × PTEN(flox/flox) mice, which enabled gene deletion using a Cre adenovirus in vitro. These mice were also immunized to generate stable Th1 clones that could have PTEN deleted when desired. PTEN-deleted T cells exhibited enhanced IL-2 production, proliferation, and Akt phosphorylation upon TCR/CD28 engagement, whereas T cell survival was not potentiated. Gene expression profiling revealed a small subset of induced genes that were augmented upon PTEN deletion. However, PTEN-deficient T cells still required CD28 costimulation for IL-2 production and remained susceptible to anti-CD3-induced anergy. The absence of PTEN within the CD8 T cell compartment led to markedly increased cytolytic activity following an allogeneic MLR in vitro, without increasing autologous MLR activity. Our results indicate that deletion of PTEN can augment the activation of postthymic T cells but does not mediate CD28 independence or anergy resistance. Nonetheless, PTEN inhibition may be a viable target for immune potentiation owing to increased cytokine production by activated CD4(+) cells and increased cytotoxicity by CD8(+) T cells.