Acceleration of apoptosis in CD4+CD8+ thymocytes by rapamycin accompanied by increased CD4+CD25+ T cells in the periphery1

Tian, Lei; Lu, Liwei; Yuan, Zhengwei; Lamb, Jonathan R.; Tam, Paul K. H.

doi:10.1097/01.tp.0000101005.44661.3e

Cited by 76 publications

(57 citation statements)

References 29 publications

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“…S6A). In accordance with previous reports (31,32), the total number of WT thymocytes was slightly reduced after 2 d of rapamycin treatment but underwent a striking 10-fold reduction 3 d later. This dramatic downfall was accompanied with a reduction of DP and mature single-positive (SP) cells.…”

Section: Rapamycin Blocks T-cell Differentiation and Thereby Halts T-allsupporting

confidence: 79%

Suppression of leukemia development caused by PTEN loss

Guo

Schubbert

Chen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Multiple genetic or molecular alterations are known to be associated with cancer stem cell formation and cancer development. Targeting such alterations, therefore, may lead to cancer prevention. By crossing our previously established phosphatase and tensin homolog (Pten)-null acute T-lymphoblastic leukemia (T-ALL) model onto the recombination-activating gene 1 −/− background, we show that the lack of variable, diversity and joining [V(D)J] recombination completely abolishes the Tcrα/δ-c-myc translocation and T-ALL development, regardless of β-catenin activation. We identify mammalian target of rapamycin (mTOR) as a regulator of β-selection. Rapamycin, an mTOR-specific inhibitor, alters nutrient sensing and blocks T-cell differentiation from CD4 − CD8 − to CD4 + CD8 + , the stage where the Tcrα/δ-c-myc translocation occurs. Long-term rapamycin treatment of preleukemic Pten-null mice prevents Tcrα/δ-c-myc translocation and leukemia stem cell (LSC) formation, and it halts T-ALL development. However, rapamycin alone fails to inhibit mTOR signaling in the c-Kit mid CD3 + Lin − population enriched for LSCs and eliminate these cells. Our results support the idea that preventing LSC formation and selectively targeting LSCs are promising approaches for antileukemia therapies. T -lymphoblastic leukemia (T-ALL) is a common hematological malignancy that is associated with poor prognosis compared with other ALLs and is often fatal without effective treatment (1). Activating mutations in Notch gene homolog 1 (NOTCH1) are reported in 34-71% of human T-ALL patients (2, 3), whereas deletion or mutations of the phosphatase and tensin homolog (PTEN). tumor suppressor gene have recently been detected in 8-63% of pediatric T-ALL patients (3-6). The mutation status of NOTCH1 and PTEN can divide pediatric T-ALL patients into three groups: (i) those with both NOTCH1 and PTEN mutations, (ii) those with NOTCH1/F-box and WD repeat domain containing 7 (FBXW7) mutations, and (iii) those with only PTEN mutations (3). Interestingly, constitutive activation of the NOTCH signaling pathway is known to down-regulate PTEN expression (5, 7), suggesting that PTEN and its controlled PI3K/v-akt murine thymoma viral oncogene homolog (AKT)/mTOR pathway are critical for the etiology of human T-ALL. Furthermore, PTEN deletion seems to be correlated with poor response to chemotherapy (6) and resistance to pharmacological inhibition of NOTCH1 (5). Therefore, understanding the molecular mechanisms of PTEN-mediated T-ALL pathogenesis and drug resistance is a critical step to improving T-ALL therapeutics.To investigate the molecular and cellular mechanisms associated with PTEN-controlled T-ALL pathogenesis and therapeutic resistance, we have recently developed a Pten loxP/loxP ;VE-CadherinCre + ;Rosa26 loxP-stop-loxP -LacZ + (Pten null) T-ALL mouse model by conditional deletion of Pten in a subset of fetal liver hematopoietic stem cells (8). The resulting animals develop a transient myeloproliferative disorder followed by T-ALL with 100% penetrance. Besides Pt...

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Section: Rapamycin Blocks T-cell Differentiation and Thereby Halts T-allsupporting

confidence: 79%

Suppression of leukemia development caused by PTEN loss

Guo

Schubbert

Chen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…ϩ Tr cell compartment (20), and its potential to expand peripheral CD4 ϩ CD25 ϩ Tr cells (21,22). Accumulation of CD4 ϩ CD25 ϩ Tr cells in the pancreas has also been previously shown in NOD mice that were rendered tolerant by different approaches (23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

Induction of Tolerance in Type 1 Diabetes via Both CD4+CD25+ T Regulatory Cells and T Regulatory Type 1 Cells

Battaglia

Stabilini

Drăghici³

et al. 2006

Diabetes

149

133

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“…A particular interesting candidate is mTOR, which promotes protein translation, glucose uptake, cell survival, and proliferation, and inhibits autophagy (35). Inhibition of mTOR by rapamycin causes death of thymocytes (36). A potential decrease of mTOR activity in the absence of DGK activity could cause death of positive selecting thymocytes.…”

Section: Discussionmentioning

confidence: 99%

Synergistic control of T cell development and tumor suppression by diacylglycerol kinase α and ζ

Guo

Wan

Carpenter

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

110

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Diacylglycerol (DAG) kinases (DGKs) are a family of enzymes that convert DAG to phosphatidic acid (PA), the physiologic functions of which have been poorly defined. We report here that DGK ␣ and synergistically promote T cell maturation in the thymus. Absence of both DGK␣ and (DGK␣ ؊/؊ ؊/؊ ) results in a severe decrease in the number of CD4 ؉ CD8 ؊ and CD4 ؊ CD8 ؉ single-positive thymocytes correlating with increased DAG-mediated signaling. Positive selection, but not negative selection, is impaired in DGK␣ ؊/؊ ؊/؊ mice. The developmental blockage in DGK␣ ؊/؊ ؊/؊ mice can be partially overcome by treatment with PA. Furthermore, decreased DGK activity also promotes thymic lymphomagenesis accompanying elevated Ras and Erk1/2 activation. Our data demonstrate a synergistic and critical role of DGK isoforms in T cell development and tumor suppression, and indicate that DGKs not only terminate DAG signaling but also initiate PA signaling in thymocytes to promote positive selection.phosphatidic acid ͉ signaling ͉ tumorigenesis D iacylglycerol (DAG) kinases (DGKs) are a family of enzymes that catalyze phosphorylation of DAG, converting it to phosphatidic acid (PA). Ten DGK isoforms have been identified in mammals and are divided into 5 subtypes based on unique structural features (1, 2). Within a single tissue, multiple DGK isoforms can be expressed. A notable feature of the DGK-mediated reaction is that both the substrate, DAG, and the product, PA, can be important second messengers. DAG can associate with Ras guanyl nucleotide-releasing proteins (RasGRPs), protein kinase Cs (PKCs), protein kinase Ds, chimaerins, and Munc-13s through their cysteine-rich (C1) domains (3). PA has been reported to bind to the SH-2 domain containing tyrosine phosphatase-1 (SHP-1), mammalian target of Rapamycin (mTOR), cAMP-specific phosphodiesterase 4 (PDE4), protein phosphatase-1 (PP-1), son of sevenless (Sos), and type I phosphatidylinositol 4-phosphate 5-kinase (PI5K) (4 -8). Through the regulation of the activities and subcellular localizations of these signaling molecules, DAG and PA play critical roles in signaling from many cell surface receptors (3, 4). It has been hypothesized that DGKs act as crucial regulators of receptor signaling and cellular function by modulating DAG and PA concentrations. However, the physiologic importance of most DGKs and the role of DGK-derived PA in receptor signaling have been poorly defined.T cell maturation in the thymus occurs through CD4 Ϫ CD8 Ϫ double-negative (DN) to CD4 ϩ CD8 ϩ double-positive (DP) and finally to the CD4 ϩ CD8 Ϫ or CD4 Ϫ CD8 ϩ single-positive (SP) stage (9). Engagement of TCR expressed on DP thymocytes with self-peptide presented by MHCs on thymic stromal cells and bone marrow-derived dendritic cells induces intracellular signaling that can lead to either maturation (positive selection) or cell death (negative selection). In general, TCRs with high affinity to self-antigens elicit strong signals directing negative selection, whereas TCRs with low affinity to self-antigens induce...

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Acceleration of apoptosis in CD4+CD8+ thymocytes by rapamycin accompanied by increased CD4+CD25+ T cells in the periphery1

Abstract: The resistance of the peripheral CD4+CD25+ T cells to Rapa treatment might contribute to its immunosuppressive action. The long-term effects of Rapa on thymus atrophy and thymocyte development requires consideration with respect to its clinical application.

Cited by 76 publications

References 29 publications

Suppression of leukemia development caused by PTEN loss

Suppression of leukemia development caused by PTEN loss

Induction of Tolerance in Type 1 Diabetes via Both CD4+CD25+ T Regulatory Cells and T Regulatory Type 1 Cells

Synergistic control of T cell development and tumor suppression by diacylglycerol kinase α and ζ

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