Pten Loss in CD4 T Cells Enhances Their Helper Function but Does Not Lead to Autoimmunity or Lymphoma

Abstract

PTEN, one of the most commonly mutated or lost tumor suppressors in human cancers, antagonizes signaling by the PI3K pathway. Mice with thymocyte-specific deletion of Pten rapidly develop peripheral lymphomas and autoimmunity, which may be caused by failed negative selection of thymocytes or from dysregulation of postthymic T cells. We induced conditional deletion of Pten from CD4 Th cells using a Cre knocked into the Tnfrsf4 (OX40) locus to generate OX40CrePtenf mice. Pten-deficient Th cells proliferated more and produced greater concentrations of cytokines. The OX40CrePtenf mice had a general increase in the number of lymphocytes in the lymph nodes, but not in the spleen. When transferred into wild-type (WT) mice, Pten-deficient Th cells enhanced anti-Listeria responses and the clearance of tumors under conditions in which WT T cells had no effect. Moreover, inflammatory responses were exaggerated and resolved later in OX40CrePtenf mice than in WT mice. However, in contrast with models of thymocyte-specific Pten deletion, lymphomas and autoimmunity were not observed, even in older OX40CrePtenf mice. Hence loss of Pten enhances Th cell function without obvious deleterious effects.