Regulation of T Cell Homeostasis and Responses by Pten

Abstract

The generation of lipid products catalyzed by PI3K is critical for normal T cell homeostasis and a productive immune response. PI3K can be activated in response to antigen receptor, co-stimulatory, cytokine, and chemokine signals. Moreover, dysregulation of this pathway frequently occurs in T cell lymphomas and is implicated in lymphoproliferative autoimmune disease. Akt acts as a central mediator of PI3K signals, downstream of which is the mTOR pathway, controlling cell growth and metabolism. Members of the Foxo family of transcription factors are also regulated by Akt, thus linking control over homing and migration of T cells, as well cell cycle entry, apoptosis, and DNA damage and oxidative stress responses, to PI3K signaling. PTEN, first identified as a tumor suppressor gene, encodes a lipid phosphatase that, by catalyzing the reverse of the PI3K “reaction,” directly opposes PI3K signaling. However, PTEN may have other functions as well, and recent reports have suggested roles for PTEN as a tumor suppressor independent of its effects on PI3K signaling. Through the use of models in which Pten is deleted specifically in T cells, it is becoming increasingly clear that control over autoimmunity and lymphomagenesis by PTEN involves multi-faceted functions of this molecule at multiple stages within the T cell compartment.

Chromatin Decondensation and T Cell Hyperresponsiveness in Diabetes-Associated Hyperglycemia

“…Stimulation of the TCR recruits and activates PI3K that modulates the activation of Akt and leads to the downstream inactivation of Forkhead box transcription factor family O (FOXO) transcription factors or mammalian target of rapamycin complex 1 (mTORC1) activation regulating T cell proliferation, growth and glycolytic metabolism (14). The increased proliferation observed in T cells from HG mice could reflect differential regulation in the Akt/mTOR pathway as well.…”

The evolution of thymic lymphomas in p53 knockout mice

“…Following the inherited p53 mutation, a Pten mutation is rapidly selected for prior to the development of mature T cells with receptors, which may also explain the decrease in the ratio of productive to nonproductive TCRb sequences (Newton and Turka 2012). While the high mutation frequency in the absence of p53 gives rise to many types of mutations, the loss of Pten metabolically permits the selection of those cells during development in the T-cell lineage (and possibly other lineages) because of its role in the insulin-like growth factor pathway.…”

Suppression of T-cell lymphomagenesis in mice requires PTEN phosphatase activity

“…[3][4][5] Mutations in PTEN are associated with multiple cancers in humans, including T-cell malignancies, [6][7][8][9][10][11][12] and targeted deletion of PTEN in murine T cells results in the development of a T-cell malignancy with characteristics of human T-cell acute lymphoblastic leukemia. [13][14][15][16] Interestingly, the most common PTEN-specific mutations that have been detected in primary T-cell acute lymphoblastic leukemia samples are mutational disruptions within the C-terminal region that do not alter phosphatase activity. 7 Moreover, a study reported spontaneous tumor development, including T-cell lymphomas, in mice harboring a knockin mutation that causes loss of the PTEN C-terminal region.…”