This information is current as Autoimmunity or Lymphoma Helper Function but Does Not Lead to Pten Loss in CD 4 T Cells Enhances Their

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 OX40 Cre Pten f mice. Pten-deficient Th cells proliferated more and produced greater concentrations of cytokines. The OX40 Cre Pten f 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 OX40 Cre Pten f mice than in WT mice. However, in contrast with models of thymocyte-specific Pten deletion, lymphomas and autoimmunity were not observed, even in older OX40 Cre Pten f mice. Hence loss of Pten enhances Th cell function without obvious deleterious effects. C D4 T cells support the coordinated activation of other leukocytes during immune responses. For instance, CD4 T cells secrete inflammatory cytokines during contact hypersensitivity (CHS) reactions, augment tumor surveillance, help B cells during the germinal center reactions, and license dendritic cells to express high levels of MHC and costimulatory ligands (1– 4). Full activation of naive CD4 T cells requires persistent stimulation of the TCR and CD28 over a period of ∼24 h. During this time, the T cells interact with APCs and integrate signals needed to increase metabolism, grow in size, and upregulate cytokine, chemokine, and costimulatory receptors (5). After initial activation , CD4 T cells begin to divide in response to cytokines and express additional costimulatory receptors such as ICOS and OX40. They then differentiate into different Th cell lineages that secrete cytokines such as IFN-g, IL-4, or IL-17. Eventually, most CD4 Th cells die through apoptosis, but some survive as CD4 memory Th cells (6). Similarly, after initial activation, naive CD8 T cells differentiate to become CTLs, and the ones that survive the cycle of expansion and contraction become CD8 memory T cells (7). The TCR and many costimulatory and cytokine receptors activate PI3Ks (8). The class I PI3Ks (p110a, p110b, p110g, and p110d) use PtdIns(4,5)P …